Neurofilament: Difference between revisions

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{{infobox protein
{{infobox protein
| Name = [[NEFL|NF-L]] neurofilament, light or low polypeptide ~68kDa
| Name = [[NEFL|NF-L]] low molecular weight neurofilament protein
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| caption =  
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| image =  
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{{infobox protein
{{infobox protein
| Name = [[NEFM|NF-M]] Neurofilament 3 145-160kDa medium or middle neurofilament subunit
| Name = [[NEFM|NF-M]] medium molecular weight neurofilament protein
| caption =  
| caption =  
| image =  
| image =  
| width =  
| width =  
| HGNCid = 7734
| HGNCid = 7734
| Symbol = NEF3
| Symbol = NEFM
| AltSymbols = NEFM
| AltSymbols = NEF3
| EntrezGene = 4741
| EntrezGene = 4741
| OMIM = 162250
| OMIM = 162250
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}}
}}
{{infobox protein
{{infobox protein
| Name = [[NEFH|NF-H]] 200-220kDa heavy or high molecular weight neurofilament subunit
| Name = [[NEFH|NF-H]] high molecular weight neurofilament protein
| caption =  
| caption =  
| image =  
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{{infobox protein
{{infobox protein
| Name = [[Alpha-internexin]] neuronal intermediate filament protein
| Name = [[Internexin|Alpha-internexin]] neuronal intermediate filament protein
| caption =  
| caption =  
| image =  
| image =  
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| Arm = q
| Arm = q
| Band = 24
| Band = 24
| LocusSupplementaryData =
}}{{infobox protein
| Name = [[Peripherin]] neuronal intermediate filament protein
| caption =
| image =
| width =
| HGNCid = 9461
| Symbol = PRPH
| AltSymbols =NEF4
| EntrezGene = 5630
| OMIM = 170710
| RefSeq = NM_006262.3
| UniProt = P41219
| PDB =
| ECnumber =
| Chromosome = 12
| Arm = q
| Band = 13.12
| LocusSupplementaryData =  
| LocusSupplementaryData =  
}}
}}
{{infobox protein
{{infobox protein
| Name = [[Nestin (protein)|Nestin]] intermediate filament subunit of neuronal stem cells
| Name = [[Nestin (protein)|Nestin]] neuronal stem cell intermediate filament protein
| caption =  
| caption =  
| image =  
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| LocusSupplementaryData =  
| LocusSupplementaryData =  
}}
}}
'''Neurofilaments''' ('''NF''') are the 10 nanometer or [[intermediate filaments]] found in [[neurons]]. They are a major component of the neuronal [[cytoskeleton]], and are believed to function primarily to provide structural support for the axon and to regulate axon diameter. Neurofilaments are composed of [[polypeptide]] chains or [[protein subunit|subunits]] which belong to the same protein family as the intermediate filaments of other tissues such as [[keratin]] subunits, which make 10&nbsp;nm filaments expressed specifically in [[epithelia]]. The family of proteins making intermediate filaments is divided into 5 major classes, the keratins forming the classes I and II. Class III contains the proteins [[vimentin]], [[desmin]], [[peripherin]] and [[glial fibrillary acidic protein]] (GFAP). The major neurofilament subunits occupy the class IV family of intermediate filaments, along with two other filament proteins of neurons, alpha-[[internexin]] and [[Nestin (protein)|nestin]]. The class IV intermediate filament genes all share two unique [[introns]] not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive class IV gene. Finally, class V corresponds to intermediate filaments of the nuclear cytoskeleton, the [[lamin|nuclear lamins]]. The term neurofibril refers to a bundle of neurofilaments.<ref>{{cite journal|last1=Löhrke|first1=S|last2=Brandstätter|first2=JH|last3=Boycott|first3=BB|last4=Peichl|first4=L|title=Expression of neurofilament proteins by horizontal cells in the rabbit retina varies with retinal location.|journal=Journal of neurocytology|date=Apr 1995|volume=24|issue=4|pages=283–300|pmid=7543937}}</ref>
'''Neurofilaments''' ('''NF''') are [[intermediate filaments]] found in the cytoplasm of [[neurons]]. They are protein polymers measuring approximately 10&nbsp;nm in diameter and many micrometers in length.  Together with [[microtubule]]s and [[microfilament]]s, they form the neuronal [[cytoskeleton]]. They are believed to function primarily to provide structural support for [[axon]]s and to regulate axon diameter, which influences nerve [[Nerve conduction velocity|conduction velocity]].  The proteins that form neurofilaments are members of the intermediate filament protein family, which is divided into 6 classes based on their gene organization and protein structure.  Class I and II are the [[keratin]]s which are expressed in epithelia. Class III contains the proteins [[vimentin]], [[desmin]], [[peripherin]] and [[glial fibrillary acidic protein]] (GFAP). Note that the neuronal intermediate filament protein peripherin, which was named by Portier and colleagues in 1983,<ref>{{cite journal | vauthors = Portier MM, Brachet P, Croizat B, Gros F | title = Regulation of peripherin in mouse neuroblastoma and rat PC 12 pheochromocytoma cell lines | journal = Developmental Neuroscience | volume = 6 | issue = 4-5 | pages = 215–26 | date = 1983 | pmid = 6151488 | doi = 10.1159/000112348 }}</ref>  should not be confused with another protein of the same name (also known as [[Peripherin 2|peripherin-2]] or peripherin-2/rds) that is expressed in the retina.  Class IV consists of the neurofilament proteins L, M, H and [[internexin]].  Class V consists of the [[Lamin|nuclear lamins]], and Class VI consists of the protein [[Nestin (protein)|nestin]]. The class IV intermediate filament genes all share two unique [[introns]] not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive class IV gene. The term neurofibril is an antiquated term that refers to the fibrous appearance of bundles of neurofilaments in nerve cells when observed in histologically stained tissue sections.<ref>{{cite journal | vauthors = Löhrke S, Brandstätter JH, Boycott BB, Peichl L | title = Expression of neurofilament proteins by horizontal cells in the rabbit retina varies with retinal location | journal = Journal of Neurocytology | volume = 24 | issue = 4 | pages = 283–300 | date = April 1995 | pmid = 7543937 }}</ref>


==Classification==
==Neurofilament proteins==
The protein composition of neurofilaments varies widely across different animal phyla. Most is known about mammalian neurofilaments.  Historically, mammalian neurofilaments were originally thought to be composed of just three proteins called neurofilament protein L (low molecular weight; NFL), M (medium molecular weight; NFM) and H (high molecular weight; NFH).  These proteins were discovered from studies of [[axonal transport]] and are often referred to as the "neurofilament triplet".<ref name=":0">{{cite journal | vauthors = Hoffman PN, Lasek RJ | title = The slow component of axonal transport. Identification of major structural polypeptides of the axon and their generality among mammalian neurons | journal = The Journal of Cell Biology | volume = 66 | issue = 2 | pages = 351–66 | date = August 1975 | pmid = 49355 | pmc = 2109569 }}</ref>  However, it is now clear that neurofilaments in the mammalian nervous system also contain the protein internexin<ref>{{cite journal | vauthors = Yuan A, Rao MV, Sasaki T, Chen Y, Kumar A, Liem RK, Eyer J, Peterson AC, Julien JP, Nixon RA | title = Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS | journal = The Journal of Neuroscience | volume = 26 | issue = 39 | pages = 10006–19 | date = September 2006 | pmid = 17005864 | doi = 10.1523/jneurosci.2580-06.2006 }}</ref> and that neurofilaments in the peripheral nervous system can also contain the protein peripherin.<ref>{{cite journal | vauthors = Yuan A, Sasaki T, Kumar A, Peterhoff CM, Rao MV, Liem RK, Julien JP, Nixon RA | title = Peripherin is a subunit of peripheral nerve neurofilaments: implications for differential vulnerability of CNS and peripheral nervous system axons | journal = The Journal of Neuroscience | volume = 32 | issue = 25 | pages = 8501–8 | date = June 2012 | pmid = 22723690 | doi = 10.1523/jneurosci.1081-12.2012 | pmc = 3405552 }}</ref>  Thus mammalian neurofilaments are heteropolymers of up to five different proteins: NFL, NFM, NFH, internexin and peripherin and it is incorrect to consider neurofilaments as being composed of just the neurofilament triplet proteins.  Moreover, it is clear that the five neurofilament proteins can coassemble in different combinations and with variable stoichiometry in different nerve cell types and at different stages of development.  The precise composition of neurofilaments in any given nerve cell depends on the relative expression levels of the neurofilament proteins in that cell at that time.  For example, NFH expression is low in developing neurons and increases postnatally in neurons that are myelinated.<ref>{{cite journal | vauthors = Nixon RA, Shea TB | title = Dynamics of neuronal intermediate filaments: a developmental perspective | journal = Cell Motility and the Cytoskeleton | volume = 22 | issue = 2 | pages = 81–91 | pmid = 1633625 | doi = 10.1002/cm.970220202 }}</ref>  In the adult nervous system neurofilaments in small unmyelinated axons contain more peripherin and less NFH whereas neurofilaments in large myelinated axons contain more NFH and less peripherin.  The Class III intermediate filament subunit, [[vimentin]], is expressed in developing neurons and a few very unusual neurons in the adult in association with Class IV proteins, such as the [[horizontal neurons]] of the [[retina]].
{| class="wikitable"
|+Human neurofilament subunit proteins
!Protein
!Amino acids
!NCBI Ref Seq
!Predicted molecular mass
!Apparent molecular mass (SDS-PAGE)
|-
|Peripherin
|470
|NP_006253.2
|53.7 kDa
|~56 kDa
|-
|Internexin
|499
|NP_116116.1
|55.4 kDa
|~66 kDa
|-
|Neurofilament protein L
|543
|NP_006149.2
|61.5 kDa
|~70 kDa
|-
|Neurofilament protein M
|916
|NP_005373.2
|102.5 kDa
|~160 kDa
|-
|Neurofilament protein H
|1020
|NP_066554.2
|111.9 kDA
|~200 kDa
|}
The triplet proteins are named based upon their relative size (low, medium, high).  The apparent [[molecular mass]] of each protein determined by [[SDS-PAGE]] is greater than the mass predicted from the amino sequence.  This is due to the anomalous electrophoretic migration of these proteins and is particularly extreme for neurofilament proteins M and H due to their high content of charged amino acids and extensive phosphorylation.  All three neurofilament triplet proteins contain long stretches of polypeptide sequence rich in [[glutamic acid]] and [[lysine]] residues, and NF-M and especially NF-H also contain multiple tandemly repeated [[serine]] phosphorylation sites. These sites almost all contain the peptide lysine-serine-proline (KSP), and phosphorylation is normally found on axonal and not dendritic neurofilaments. Human NF-M has 13 of these KSP sites, while human NF-H is expressed from two [[allele]]s one of which produces 44 and the other 45 KSP repeats.


=== Subunit proteins ===
== Neurofilament assembly and structure ==
The three major neurofilament subunits were discovered from studies of [[axonal transport]]. Proteins are synthesized within the cell body, and hence they must travel along the axon to reach their final destination. The names given to the three major neurofilament subunits are based upon the apparent [[molecular mass]] of the [[mammal]]ian subunits on [[SDS-PAGE]]:
[[File:Neuron in tissue culture.jpg|thumb|Rat brain cells grown in [[tissue culture]] and stained, in green, with an antibody to neurofilament subunit NF-L, which reveals a large neuron. The culture was stained in red for alpha-internexin, which in this culture is found in neuronal stem cells surrounding the large neuron. Image courtesy of [[EnCor Biotechnology Inc.]]]]
 
* the light or lowest (NF-L) runs at 68-70 [[kDa]]
* the medium or middle (NF-M) runs at about 145-160 kDa
* the heavy or highest (NF-H) runs at 200-220 kDa
 
These three proteins are often referred to as the "neurofilament triplet", and numerous specific [[antibodies]] to these proteins have been developed and made commercially available. Such antibodies are widely used to identify neurons and their processes in [[histological section]]s and in [[tissue culture]]. The [[SDS-PAGE]] molecular masses of the triplet proteins vary between mammalian species, with larger species usually having larger proteins. The real molecular masses of these proteins are considerably lower than estimated based on SDS-PAGE mobility, particularly in the case of NF-H and NF-M. This is due to the highly charged [[C-terminus|C-terminal]] regions of the [[molecule]]s. All three triplet proteins contain long stretches of polypeptide sequence rich in [[glutamic acid]] residues, and NF-M and especially NF-H also contain multiple tandemly repeated [[serine]] phosphorylation sites. These sites almost all contain the peptide lysine-serine-proline (KSP), and phosphorylation is normally found on axonal and not dendritic neurofilaments. Human NF-M has 13 of these KSP sites, while human NF-H is expressed from two [[allele]]s one of which produces 44 and the other 45 KSP repeats. Neurofilaments are found in [[vertebrate]] neurons in especially high concentrations in axons, where they appear to provide mechanical strength and regulate axonal diameter.
 
The fourth class IV subunit, alpha-internexin (NF66) was discovered much later than NF-L, NF-M and NF-H, and is found co-polymerized with these proteins in most mature neurons. It is generally expressed earlier in development than the other neurofilament proteins and may be found in some neurons in the apparent absence of the neurofilament triplet.


The fifth protein belonging to class IV, Nestin, is found in developing neurons and glia, and the presence of this protein is widely used to define [[neurogenesis]]. This protein is lost as development proceeds.
Like other intermediate filament proteins, the neurofilament proteins all share a common central alpha helical region, known as the rod domain because of its rod-like tertiary structure, flanked by [[N-terminus|amino terminal]] and [[C-terminus|carboxy terminal]] domains that are largely unstructured.  The rod domains of two neurofilament proteins dimerize to form an alpha-helical [[coiled coil]]. Two dimers associate in a staggered antiparallel manner to form a tetramer.  This tetramer is believed to be the basic subunit (i.e. building block) of the neurofilament.  Tetramer subunits associate side-to-side to form unit-length filaments, which then anneal end-to-end to form the mature neurofilament polymer, but the precise organization of these subunits within the polymer is not known, largely because of the heterogeneous protein composition and the inability to crystallize neurofilaments or neurofilament proteins.  Structural models generally assume eight tetramers (32 neurofilament polypeptides) in a filament cross-section, but measurements of linear mass density suggest that this can vary.


The class III intermediate filament protein subunit [[peripherin]] is found in neurofilaments along with the class IV subunits in a few neurons, mostly in the [[peripheral nervous system]]. Finally another class III intermediate filament subunit, [[vimentin]], is found in developing neurons and a few very unusual neurons in the adult in association with class IV proteins, such as the [[horizontal neurons]] of the [[retina]].
The amino terminal domains of the neurofilament proteins contain numerous phosphorylation sites and appear to be important for subunit interactions during filament assembly.  The carboxy terminal domains appear to be intrinsically disordered domains that lack alpha helix or beta sheet.  The different sizes of the neurofilament proteins are largely due to differences in the length of the carboxy terminal domains.  These domains are rich in acidic and basic amino acid residues.  The carboxy terminal domains of NFM and NFH are the longest and are modified extensively by post-translational modifications such as [[phosphorylation]] and [[glycosylation]] in vivo.  They project radially from the filament backbone to form a dense brush border of highly charged and unstructured domains analogous to the bristles on a bottle brush.  These entropically flailing domains have been proposed to define a zone of exclusion around each filament, effectively spacing the filaments apart from their neighbors.  In this way, the carboxy terminal projections maximize the space-filling properties of the neurofilament polymers.  By electron microscopy, these domains appear as projections called sidearms that appear to contact neighboring filaments.[[File:Mouse NT antibody NF Ki67.jpg|thumb|[[Antibody]] [[staining|stain]] against neurofilament (green) and [[Ki-67 (protein)|Ki 67]] (red) in a mouse [[embryo]] 12.5 days after [[fertilization]]. The cells expressing neurofilaments are in the [[dorsal root ganglia]] shown in green while [[cell growth|proliferating cells]] are in the [[ventricular system|ventricular zone]] in the [[neural tube]] and colored red.]]


In the adult mammal neurofilament subunit proteins coassemble ''[[in vivo]]'', forming a [[heteropolymer]] that contain NF-L or alpha-internexin plus NF-M or NF-H. Peripherin and vimentin may incorporate into neurofilaments along with these proteins. The NF-H and NF-M proteins have lengthy C-terminal tail domains that appear to control the spacing between neighboring filaments, generating aligned arrays with a fairly uniform interfilament spacing as seen in axons.
== Neurofilament function ==
Neurofilaments are found in [[vertebrate]] neurons in especially high concentrations in axons, where they are all aligned in parallel along the long axis of the axon forming a continuously overlapping array.  They have been proposed to function as space-filling structures that increase axonal diameter.  Their contribution to axon diameter is determined by the number of neurofilaments in the axon and their packing density. The number of neurofilaments in the axon is thought to be determined by neurofilament gene expression <ref>{{cite book |title=Molecular biology of the cell |publisher=Garland Science |isbn=0-8153-3218-1 |edition=4th}}</ref> and axonal transport. The packing density of the filaments is determined by their side-arms which define the spacing between neighboring filaments.  Phosphorylation of the sidearms is thought to increase their extensibility, increasing the spacing between neighboring filaments <ref>{{cite journal |last1=Eyer |first1=J |last2=Leterrier |first2=J F |title=Influence of the phosphorylation state of neurofilament proteins on the interactions between purified filaments |journal=Biochemical Journal |date=15 June 1988 |volume=252 |issue=3 |pages=655–660 |doi=10.1042/bj2520655}}</ref> by the binding of divalent cations between the sidearms of adjacent filaments <ref>{{cite journal | vauthors = Kushkuley J, Chan WK, Lee S, Eyer J, Leterrier JF, Letournel F, Shea TB | title = Neurofilament cross-bridging competes with kinesin-dependent association of neurofilaments with microtubules | journal = Journal of Cell Science | volume = 122 | issue = Pt 19 | pages = 3579–86 | date = October 2009 | pmid = 19737816 | doi = 10.1242/jcs.051318 }}</ref><ref>{{cite journal | vauthors = Kushkuley J, Metkar S, Chan WK, Lee S, Shea TB | title = Aluminum induces neurofilament aggregation by stabilizing cross-bridging of phosphorylated c-terminal sidearms | journal = Brain Research | volume = 1322 | issue =  | pages = 118–23 | date = March 2010 | pmid = 20132798 | doi = 10.1016/j.brainres.2010.01.075 }}</ref>


==Growth==
Early in development, axons are narrow processes that contain relatively few neurofilaments. Those axons that become myelinated accumulate more neurofilaments, which drives the expansion of their caliber.  After an axon has grown and connected with its [[target cell]], the diameter of the axon may increase as much as fivefold<!--{{Citation needed}} begin-->{{fix |link=Wikipedia:Citation needed#Citation needed |text=citation needed |class=Template-Fact }}<!--{{Citation needed}} end-->. This is caused by an increase in the number of neurofilaments exported from the nerve cell body as well as a slowing of their rate of transport.  In mature myelinated axons, neurofilaments can be the single most abundant cytoplasmic structure and can occupy most of the axonal cross-sectional area. For example, a large myelinated axon may contain thousands of neurofilaments in one cross-section.
[[File:Mouse NT antibody NF Ki67.jpg|thumb|[[Antibody]] [[staining|stain]] against neurofilament (green) and [[Ki-67 (protein)|Ki 67]] (red) in a mouse [[embryo]] 12.5 days after [[fertilization]]. The cells expressing neurofilaments are in the [[dorsal root ganglia]] shown in green while [[cell growth|proliferating cells]] are in the [[ventricular system|ventricular zone]] in the [[neural tube]] and colored red.]]
During axonal growth, new neurofilament subunits are incorporated all along the axon in a dynamic process that involves the addition of subunits along the filament length, as well as the addition of subunits at the filament ends.
 
[[File:Neuron in tissue culture.jpg|thumb|Rat brain cells grown in [[tissue culture]] and stained, in green, with an antibody to neurofilament subunit NF-L, which reveals a large neuron. The culture was stained in red for alpha-internexin, which in this culture is found in neuronal stem cells surrounding the large neuron. Image courtesy of [[EnCor Biotechnology Inc.]]]]


After an axon has grown and connected with its [[target cell]], the diameter of the axon may increase as much as fivefold<!--{{Citation needed}} begin-->{{fix |link=Wikipedia:Citation needed#Citation needed |text=citation needed |class=Template-Fact }}<!--{{Citation needed}} end-->.
[[mutation|Mutant]] mice with neurofilament abnormalities have [[phenotypes]] resembling [[amyotrophic lateral sclerosis]].<ref name="pmid14640321">{{cite journal | vauthors = Lalonde R, Strazielle C | title = Neurobehavioral characteristics of mice with modified intermediate filament genes | journal = Reviews in the Neurosciences | volume = 14 | issue = 4 | pages = 369–85 | year = 2003 | pmid = 14640321 | doi = 10.1515/REVNEURO.2003.14.4.369 }}</ref>[[File:Central chromatolysis - nf - high mag.jpg|thumb|right|[[Micrograph]] of [[white matter]] (bottom of image) and the [[anterior horn of spinal cord|anterior horn of the spinal cord]] showing [[motor neuron]]s with [[central chromatolysis]]. [[w:Neurofilament|Neurofilament]] [[w:immunostain|immunostain]].]]


Phosphorylation is thought to contribute to the neurofilament-mediated increase of axonal caliber<ref>Eyer J., Leterrier J. F. (1988). Influence of the phosphorylation state of neurofilament proteins on the interactions between purified filaments in vitro. Biochem. J. 252, 655–660</ref><ref>Gou J. P., Gotow T., Janmey P. A., Leterrier J. F. (1998). Regulation of neurofilament interactions in vitro by natural and synthetic polypeptides sharing Lys-Ser-Pro sequences with the heavy neurofilament subunit NF-H: neurofilament [[crossbridging]] by antiparallel sidearm overlapping. Med. Biol. Eng. Comput. 36, 371–387 10.1007/BF02522486</ref> by the binding of divalent cations between the sidearms of adjacent filaments<ref>Kushkuley J., Chan W. K., Lee S., Eyer J., Leterrier J. F., Letournel F., Shea T. B. (2009). Neurofilament cross-bridging competes with kinesin-dependent association of neurofilaments with microtubules. J. Cell Sci. 122, 3579–3586 10.1242/jcs.051318</ref><ref>Kushkuley J., Metkar S., Chan W. K., Lee S., Shea T. B. (2010). Aluminum induces neurofilament aggregation by stabilizing cross-bridging of phosphorylated c-terminal sidearms. Brain Res. 1322, 118–123 10.1016/j.brainres.2010.01.075</ref>
==  Neurofilament transport ==
In addition to their structural role in axons, neurofilaments are also cargoes of [[axonal transport]].<ref name=":0" /> Most of the neurofilament proteins in axons are synthesized in the nerve cell body, where they rapidly assemble into neurofilament polymers within about 30 minutes.<ref>{{cite journal | vauthors = Black MM, Keyser P, Sobel E | title = Interval between the synthesis and assembly of cytoskeletal proteins in cultured neurons | journal = The Journal of Neuroscience | volume = 6 | issue = 4 | pages = 1004–12 | date = April 1986 | pmid = 3084715 }}</ref>  These assembled neurofilament polymers are transported along the axon on [[microtubule]] tracks powered by microtubule [[motor protein]]s.<ref>{{cite journal | vauthors = Wang L, Ho CL, Sun D, Liem RK, Brown A | title = Rapid movement of axonal neurofilaments interrupted by prolonged pauses | journal = Nature Cell Biology | volume = 2 | issue = 3 | pages = 137–41 | date = March 2000 | pmid = 10707083 | doi = 10.1038/35004008 }}</ref>   The filaments move bidirectionally, i.e. both towards the axon tip (anterograde) and towards the cell body (retrograde), but the net direction is anterograde. The filaments move at velocities of up to 8&nbsp;µm/s on short time scales (seconds or minutes), with average velocities of approximately 1&nbsp;µm/s.<ref>{{cite journal | vauthors = Fenn JD, Johnson CM, Peng J, Jung P, Brown A | title = Kymograph analysis with high temporal resolution reveals new features of neurofilament transport kinetics | journal = Cytoskeleton | volume = 75 | issue = 1 | pages = 22–41 | date = January 2018 | pmid = 28926211 | doi = 10.1002/cm.21411 }}</ref> However, the average velocity on longer time scales (hours or days) is slow because the movements are very infrequent, consisting of brief sprints interrupted by long pauses.<ref>{{cite journal | vauthors = Brown A | title = Slow axonal transport: stop and go traffic in the axon | journal = Nature Reviews. Molecular Cell Biology | volume = 1 | issue = 2 | pages = 153–6 | date = November 2000 | pmid = 11253369 | doi = 10.1038/35040102 }}</ref><ref>{{cite journal | vauthors = Brown A, Wang L, Jung P | title = Stochastic simulation of neurofilament transport in axons: the "stop-and-go" hypothesis | journal = Molecular Biology of the Cell | volume = 16 | issue = 9 | pages = 4243–55 | date = September 2005 | pmid = 16000374 | pmc = 1196334 | doi = 10.1091/mbc.E05-02-0141 }}</ref> Thus on long time scales neurofilaments move in the slow component of axonal transport.


The level of neurofilament [[gene expression]] seems to directly control axonal diameter, which in turn controls how fast electrical signals travel down the axon.<ref name="isbn0-8153-3218-1">{{cite book | author = Alberts, Bruce | authorlink = | editor = | others = | title = Molecular biology of the cell | edition = 4th | language = | publisher = Garland Science | location = New York | year = 2002 | origyear = | pages = | quote = | isbn = 0-8153-3218-1 | oclc = | doi = | url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4 | accessdate = }}</ref>
== Clinical and research applications ==
Numerous specific [[antibodies]] to neurofilament proteins have been developed and are commercially available.  These antibodies can be used to detect neurofilament proteins in cells and tissues using [[immunofluorescence]] microscopy or [[immunohistochemistry]].  Such antibodies are widely used to identify neurons and their processes in [[histological section]]s and in [[tissue culture]].  The Class VI intermediate filament protein nestin is expressed in developing neurons and glia. Nestin is considered a marker of neuronal stem cells, and the presence of this protein is widely used to define [[neurogenesis]]. This protein is lost as development proceeds.


[[mutation|Mutant]] mice with neurofilament abnormalities have [[phenotypes]] resembling [[amyotrophic lateral sclerosis]].<ref name="pmid14640321">{{cite journal | author = Lalonde R, Strazielle C | title = Neurobehavioral characteristics of mice with modified intermediate filament genes | journal = Rev Neurosci | volume = 14 | issue = 4 | pages = 369–85 | year = 2003 | pmid = 14640321 | doi = 10.1515/REVNEURO.2003.14.4.369| url =  | last2 = Strazielle }}</ref>
Neurofilament antibodies are also commonly used in diagnostic [[neuropathology]].  Staining with these antibodies can distinguish neurons (positive for neurofilament proteins) from [[glia]] (negative for neurofilament proteins).


== Use in diagnostic pathology ==
There is also considerable clinical interest in the use of neurofilament proteins as biomarkers of axonal damage in neurodegenerative diseases.  When neurons or axons degenerate, neurofilament proteins are released into the blood or cerebrospinal fluid. Immunoassays of neurofilament proteins in cerebrospinal fluid and plasma can thus serve as indicators of axonal damage in neurological disorders.<ref>{{cite journal | vauthors = Jonsson M, Zetterberg H, van Straaten E, Lind K, Syversen S, Edman A, Blennow K, Rosengren L, Pantoni L, Inzitari D, Wallin A | title = Cerebrospinal fluid biomarkers of white matter lesions - cross-sectional results from the LADIS study | journal = European Journal of Neurology | volume = 17 | issue = 3 | pages = 377–82 | date = March 2010 | pmid = 19845747 | doi = 10.1111/j.1468-1331.2009.02808.x }}</ref> NFL is a useful marker for disease monitoring in Amyotrophic Lateral Sclerosis,<ref>{{cite journal | vauthors = Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelsø C | title = Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF | journal = Journal of Neurochemistry | volume = 67 | issue = 5 | pages = 2013–8 | date = November 1996 | pmid = 8863508 | doi = 10.1046/j.1471-4159.1996.67052013.x }}</ref> multiple sclerosis<ref>{{cite journal | vauthors = Teunissen CE, Iacobaeus E, Khademi M, Brundin L, Norgren N, Koel-Simmelink MJ, Schepens M, Bouwman F, Twaalfhoven HA, Blom HJ, Jakobs C, Dijkstra CD | title = Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis | journal = Neurology | volume = 72 | issue = 15 | pages = 1322–9 | date = April 2009 | pmid = 19365053 | doi = 10.1212/wnl.0b013e3181a0fe3f }}</ref> and more recently Huntington's disease.<ref>{{cite journal | vauthors = Niemelä V, Landtblom AM, Blennow K, Sundblom J | title = Tau or neurofilament light-Which is the more suitable biomarker for Huntington's disease? | journal = PLOS One | volume = 12 | issue = 2 | pages = e0172762 | date = 27 February 2017 | pmid = 28241046 | pmc = 5328385 | doi = 10.1371/journal.pone.0172762 }}</ref>
[[File:Central chromatolysis - nf - high mag.jpg|thumb|right|[[Micrograph]] of [[white matter]] (bottom of image) and the [[anterior horn of spinal cord|anterior horn of the spinal cord]] showing [[motor neuron]]s with [[central chromatolysis]]. [[w:Neurofilament|Neurofilament]] [[w:immunostain|immunostain]].]]
Neurofilament, NF, [[immunostain]]ing is common in diagnostic [[neuropathology]].  It is useful for differentiating neurons (positive for NF) from [[glia]] (negative for NF). The Neurofilament light subunit can be measured with immunoassays in cerebrospinal fluid and plasma and reflects axonal damage in neurological disorders.<ref>{{cite journal|last1=Jonsson|first1=M.|last2=Zetterberg|first2=H.|last3=Van Straaten|first3=E.|last4=Lind|first4=K.|last5=Syversen|first5=S.|last6=Edman|first6=Å.|last7=Blennow|first7=K.|last8=Rosengren|first8=L.|last9=Pantoni|first9=L.|last10=Inzitari|first10=D.|last11=Wallin|first11=A.|title=Cerebrospinal fluid biomarkers of white matter lesions - cross-sectional results from the LADIS study|journal=European Journal of Neurology|date=March 2010|volume=17|issue=3|pages=377–382|doi=10.1111/j.1468-1331.2009.02808.x|pmid= 19845747}}</ref> It is a useful maker for disease monitoring in Amyotrophic Lateral Sclerosis,<ref>{{cite journal|last1=Rosengren|first1=LE|last2=Karlsson|first2=JE|last3=Karlsson|first3=JO|last4=Persson|first4=LI|last5=Wikkelsø|first5=C|title=Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF.|journal=Journal of Neurochemistry|date=November 1996|volume=67|issue=5|pages=2013–8|pmid=8863508}}</ref> multiple sclerosis<ref>{{cite journal|last1=Teunissen|first1=CE|last2=Iacobaeus|first2=E|last3=Khademi|first3=M|last4=Brundin|first4=L|last5=Norgren|first5=N|last6=Koel-Simmelink|first6=MJ|last7=Schepens|first7=M|last8=Bouwman|first8=F|last9=Twaalfhoven|first9=HA|last10=Blom|first10=HJ|last11=Jakobs|first11=C|last12=Dijkstra|first12=CD|title=Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis.|journal=Neurology|date=14 April 2009|volume=72|issue=15|pages=1322–9|pmid=19365053}}</ref> and more recently Huntingtons disease.<ref>{{cite journal|last1=Niemelä|first1=Valter|last2=Landtblom|first2=Anne-Marie|last3=Blennow|first3=Kaj|last4=Sundblom|first4=Jimmy|last5=Blum|first5=David|title=Tau or neurofilament light—Which is the more suitable biomarker for Huntington’s disease?|journal=PLOS ONE|date=27 February 2017|volume=12|issue=2|pages=e0172762|doi=10.1371/journal.pone.0172762}}</ref>


== See also ==
== See also ==
Line 137: Line 184:
* [[Bielschowsky stain]]
* [[Bielschowsky stain]]


==References==
== References ==
{{Reflist}}
{{Reflist}}


Revision as of 22:33, 2 January 2019

NF-L low molecular weight neurofilament protein
Identifiers
SymbolNEFL
Entrez4747
HUGO7739
OMIM162280
RefSeqNM_006158
UniProtP07196
Other data
LocusChr. 8 p21
NF-M medium molecular weight neurofilament protein
Identifiers
SymbolNEFM
Alt. symbolsNEF3
Entrez4741
HUGO7734
OMIM162250
RefSeqNM_005382
UniProtP07197
Other data
LocusChr. 8 p21
NF-H high molecular weight neurofilament protein
Identifiers
SymbolNEFH
Entrez4744
HUGO7737
OMIM162230
RefSeqNM_021076
UniProtP12036
Other data
LocusChr. 22 q12.1-13.1
Alpha-internexin neuronal intermediate filament protein
Identifiers
SymbolINA
Alt. symbolsNEF5
Entrez9118
HUGO6057
OMIM605338
RefSeqNM_032727
UniProtQ5SYD2
Other data
LocusChr. 10 q24
Peripherin neuronal intermediate filament protein
Identifiers
SymbolPRPH
Alt. symbolsNEF4
Entrez5630
HUGO9461
OMIM170710
RefSeqNM_006262.3
UniProtP41219
Other data
LocusChr. 12 q13.12
Nestin neuronal stem cell intermediate filament protein
Identifiers
SymbolNES
Entrez10763
HUGO7756
OMIM600915
RefSeqNP_006608
UniProtP48681
Other data
LocusChr. 1 q23.1

Neurofilaments (NF) are intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring approximately 10 nm in diameter and many micrometers in length. Together with microtubules and microfilaments, they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. The proteins that form neurofilaments are members of the intermediate filament protein family, which is divided into 6 classes based on their gene organization and protein structure. Class I and II are the keratins which are expressed in epithelia. Class III contains the proteins vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP). Note that the neuronal intermediate filament protein peripherin, which was named by Portier and colleagues in 1983,[1] should not be confused with another protein of the same name (also known as peripherin-2 or peripherin-2/rds) that is expressed in the retina. Class IV consists of the neurofilament proteins L, M, H and internexin. Class V consists of the nuclear lamins, and Class VI consists of the protein nestin. The class IV intermediate filament genes all share two unique introns not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive class IV gene. The term neurofibril is an antiquated term that refers to the fibrous appearance of bundles of neurofilaments in nerve cells when observed in histologically stained tissue sections.[2]

Neurofilament proteins

The protein composition of neurofilaments varies widely across different animal phyla. Most is known about mammalian neurofilaments. Historically, mammalian neurofilaments were originally thought to be composed of just three proteins called neurofilament protein L (low molecular weight; NFL), M (medium molecular weight; NFM) and H (high molecular weight; NFH). These proteins were discovered from studies of axonal transport and are often referred to as the "neurofilament triplet".[3] However, it is now clear that neurofilaments in the mammalian nervous system also contain the protein internexin[4] and that neurofilaments in the peripheral nervous system can also contain the protein peripherin.[5] Thus mammalian neurofilaments are heteropolymers of up to five different proteins: NFL, NFM, NFH, internexin and peripherin and it is incorrect to consider neurofilaments as being composed of just the neurofilament triplet proteins. Moreover, it is clear that the five neurofilament proteins can coassemble in different combinations and with variable stoichiometry in different nerve cell types and at different stages of development. The precise composition of neurofilaments in any given nerve cell depends on the relative expression levels of the neurofilament proteins in that cell at that time. For example, NFH expression is low in developing neurons and increases postnatally in neurons that are myelinated.[6] In the adult nervous system neurofilaments in small unmyelinated axons contain more peripherin and less NFH whereas neurofilaments in large myelinated axons contain more NFH and less peripherin. The Class III intermediate filament subunit, vimentin, is expressed in developing neurons and a few very unusual neurons in the adult in association with Class IV proteins, such as the horizontal neurons of the retina.

Human neurofilament subunit proteins
Protein Amino acids NCBI Ref Seq Predicted molecular mass Apparent molecular mass (SDS-PAGE)
Peripherin 470 NP_006253.2 53.7 kDa ~56 kDa
Internexin 499 NP_116116.1 55.4 kDa ~66 kDa
Neurofilament protein L 543 NP_006149.2 61.5 kDa ~70 kDa
Neurofilament protein M 916 NP_005373.2 102.5 kDa ~160 kDa
Neurofilament protein H 1020 NP_066554.2 111.9 kDA ~200 kDa

The triplet proteins are named based upon their relative size (low, medium, high). The apparent molecular mass of each protein determined by SDS-PAGE is greater than the mass predicted from the amino sequence. This is due to the anomalous electrophoretic migration of these proteins and is particularly extreme for neurofilament proteins M and H due to their high content of charged amino acids and extensive phosphorylation. All three neurofilament triplet proteins contain long stretches of polypeptide sequence rich in glutamic acid and lysine residues, and NF-M and especially NF-H also contain multiple tandemly repeated serine phosphorylation sites. These sites almost all contain the peptide lysine-serine-proline (KSP), and phosphorylation is normally found on axonal and not dendritic neurofilaments. Human NF-M has 13 of these KSP sites, while human NF-H is expressed from two alleles one of which produces 44 and the other 45 KSP repeats.

Neurofilament assembly and structure

File:Neuron in tissue culture.jpg
Rat brain cells grown in tissue culture and stained, in green, with an antibody to neurofilament subunit NF-L, which reveals a large neuron. The culture was stained in red for alpha-internexin, which in this culture is found in neuronal stem cells surrounding the large neuron. Image courtesy of EnCor Biotechnology Inc.

Like other intermediate filament proteins, the neurofilament proteins all share a common central alpha helical region, known as the rod domain because of its rod-like tertiary structure, flanked by amino terminal and carboxy terminal domains that are largely unstructured. The rod domains of two neurofilament proteins dimerize to form an alpha-helical coiled coil. Two dimers associate in a staggered antiparallel manner to form a tetramer. This tetramer is believed to be the basic subunit (i.e. building block) of the neurofilament. Tetramer subunits associate side-to-side to form unit-length filaments, which then anneal end-to-end to form the mature neurofilament polymer, but the precise organization of these subunits within the polymer is not known, largely because of the heterogeneous protein composition and the inability to crystallize neurofilaments or neurofilament proteins. Structural models generally assume eight tetramers (32 neurofilament polypeptides) in a filament cross-section, but measurements of linear mass density suggest that this can vary.

The amino terminal domains of the neurofilament proteins contain numerous phosphorylation sites and appear to be important for subunit interactions during filament assembly. The carboxy terminal domains appear to be intrinsically disordered domains that lack alpha helix or beta sheet. The different sizes of the neurofilament proteins are largely due to differences in the length of the carboxy terminal domains. These domains are rich in acidic and basic amino acid residues. The carboxy terminal domains of NFM and NFH are the longest and are modified extensively by post-translational modifications such as phosphorylation and glycosylation in vivo. They project radially from the filament backbone to form a dense brush border of highly charged and unstructured domains analogous to the bristles on a bottle brush. These entropically flailing domains have been proposed to define a zone of exclusion around each filament, effectively spacing the filaments apart from their neighbors. In this way, the carboxy terminal projections maximize the space-filling properties of the neurofilament polymers. By electron microscopy, these domains appear as projections called sidearms that appear to contact neighboring filaments.

File:Mouse NT antibody NF Ki67.jpg
Antibody stain against neurofilament (green) and Ki 67 (red) in a mouse embryo 12.5 days after fertilization. The cells expressing neurofilaments are in the dorsal root ganglia shown in green while proliferating cells are in the ventricular zone in the neural tube and colored red.

Neurofilament function

Neurofilaments are found in vertebrate neurons in especially high concentrations in axons, where they are all aligned in parallel along the long axis of the axon forming a continuously overlapping array. They have been proposed to function as space-filling structures that increase axonal diameter. Their contribution to axon diameter is determined by the number of neurofilaments in the axon and their packing density. The number of neurofilaments in the axon is thought to be determined by neurofilament gene expression [7] and axonal transport. The packing density of the filaments is determined by their side-arms which define the spacing between neighboring filaments. Phosphorylation of the sidearms is thought to increase their extensibility, increasing the spacing between neighboring filaments [8] by the binding of divalent cations between the sidearms of adjacent filaments [9][10]

Early in development, axons are narrow processes that contain relatively few neurofilaments. Those axons that become myelinated accumulate more neurofilaments, which drives the expansion of their caliber. After an axon has grown and connected with its target cell, the diameter of the axon may increase as much as fivefold[citation needed]. This is caused by an increase in the number of neurofilaments exported from the nerve cell body as well as a slowing of their rate of transport. In mature myelinated axons, neurofilaments can be the single most abundant cytoplasmic structure and can occupy most of the axonal cross-sectional area. For example, a large myelinated axon may contain thousands of neurofilaments in one cross-section.

Mutant mice with neurofilament abnormalities have phenotypes resembling amyotrophic lateral sclerosis.[11]

File:Central chromatolysis - nf - high mag.jpg
Micrograph of white matter (bottom of image) and the anterior horn of the spinal cord showing motor neurons with central chromatolysis. Neurofilament immunostain.

Neurofilament transport

In addition to their structural role in axons, neurofilaments are also cargoes of axonal transport.[3] Most of the neurofilament proteins in axons are synthesized in the nerve cell body, where they rapidly assemble into neurofilament polymers within about 30 minutes.[12] These assembled neurofilament polymers are transported along the axon on microtubule tracks powered by microtubule motor proteins.[13] The filaments move bidirectionally, i.e. both towards the axon tip (anterograde) and towards the cell body (retrograde), but the net direction is anterograde. The filaments move at velocities of up to 8 µm/s on short time scales (seconds or minutes), with average velocities of approximately 1 µm/s.[14] However, the average velocity on longer time scales (hours or days) is slow because the movements are very infrequent, consisting of brief sprints interrupted by long pauses.[15][16] Thus on long time scales neurofilaments move in the slow component of axonal transport.

Clinical and research applications

Numerous specific antibodies to neurofilament proteins have been developed and are commercially available. These antibodies can be used to detect neurofilament proteins in cells and tissues using immunofluorescence microscopy or immunohistochemistry. Such antibodies are widely used to identify neurons and their processes in histological sections and in tissue culture. The Class VI intermediate filament protein nestin is expressed in developing neurons and glia. Nestin is considered a marker of neuronal stem cells, and the presence of this protein is widely used to define neurogenesis. This protein is lost as development proceeds.

Neurofilament antibodies are also commonly used in diagnostic neuropathology. Staining with these antibodies can distinguish neurons (positive for neurofilament proteins) from glia (negative for neurofilament proteins).

There is also considerable clinical interest in the use of neurofilament proteins as biomarkers of axonal damage in neurodegenerative diseases. When neurons or axons degenerate, neurofilament proteins are released into the blood or cerebrospinal fluid. Immunoassays of neurofilament proteins in cerebrospinal fluid and plasma can thus serve as indicators of axonal damage in neurological disorders.[17] NFL is a useful marker for disease monitoring in Amyotrophic Lateral Sclerosis,[18] multiple sclerosis[19] and more recently Huntington's disease.[20]

See also

References

  1. ↑ Portier MM, Brachet P, Croizat B, Gros F (1983). "Regulation of peripherin in mouse neuroblastoma and rat PC 12 pheochromocytoma cell lines". Developmental Neuroscience. 6 (4–5): 215–26. doi:10.1159/000112348. PMID 6151488.
  2. ↑ Löhrke S, Brandstätter JH, Boycott BB, Peichl L (April 1995). "Expression of neurofilament proteins by horizontal cells in the rabbit retina varies with retinal location". Journal of Neurocytology. 24 (4): 283–300. PMID 7543937.
  3. ↑ 3.0 3.1 Hoffman PN, Lasek RJ (August 1975). "The slow component of axonal transport. Identification of major structural polypeptides of the axon and their generality among mammalian neurons". The Journal of Cell Biology. 66 (2): 351–66. PMC 2109569. PMID 49355.
  4. ↑ Yuan A, Rao MV, Sasaki T, Chen Y, Kumar A, Liem RK, Eyer J, Peterson AC, Julien JP, Nixon RA (September 2006). "Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS". The Journal of Neuroscience. 26 (39): 10006–19. doi:10.1523/jneurosci.2580-06.2006. PMID 17005864.
  5. ↑ Yuan A, Sasaki T, Kumar A, Peterhoff CM, Rao MV, Liem RK, Julien JP, Nixon RA (June 2012). "Peripherin is a subunit of peripheral nerve neurofilaments: implications for differential vulnerability of CNS and peripheral nervous system axons". The Journal of Neuroscience. 32 (25): 8501–8. doi:10.1523/jneurosci.1081-12.2012. PMC 3405552. PMID 22723690.
  6. ↑ Nixon RA, Shea TB. "Dynamics of neuronal intermediate filaments: a developmental perspective". Cell Motility and the Cytoskeleton. 22 (2): 81–91. doi:10.1002/cm.970220202. PMID 1633625.
  7. ↑ Molecular biology of the cell (4th ed.). Garland Science. ISBN 0-8153-3218-1.
  8. ↑ Eyer, J; Leterrier, J F (15 June 1988). "Influence of the phosphorylation state of neurofilament proteins on the interactions between purified filaments". Biochemical Journal. 252 (3): 655–660. doi:10.1042/bj2520655.
  9. ↑ Kushkuley J, Chan WK, Lee S, Eyer J, Leterrier JF, Letournel F, Shea TB (October 2009). "Neurofilament cross-bridging competes with kinesin-dependent association of neurofilaments with microtubules". Journal of Cell Science. 122 (Pt 19): 3579–86. doi:10.1242/jcs.051318. PMID 19737816.
  10. ↑ Kushkuley J, Metkar S, Chan WK, Lee S, Shea TB (March 2010). "Aluminum induces neurofilament aggregation by stabilizing cross-bridging of phosphorylated c-terminal sidearms". Brain Research. 1322: 118–23. doi:10.1016/j.brainres.2010.01.075. PMID 20132798.
  11. ↑ Lalonde R, Strazielle C (2003). "Neurobehavioral characteristics of mice with modified intermediate filament genes". Reviews in the Neurosciences. 14 (4): 369–85. doi:10.1515/REVNEURO.2003.14.4.369. PMID 14640321.
  12. ↑ Black MM, Keyser P, Sobel E (April 1986). "Interval between the synthesis and assembly of cytoskeletal proteins in cultured neurons". The Journal of Neuroscience. 6 (4): 1004–12. PMID 3084715.
  13. ↑ Wang L, Ho CL, Sun D, Liem RK, Brown A (March 2000). "Rapid movement of axonal neurofilaments interrupted by prolonged pauses". Nature Cell Biology. 2 (3): 137–41. doi:10.1038/35004008. PMID 10707083.
  14. ↑ Fenn JD, Johnson CM, Peng J, Jung P, Brown A (January 2018). "Kymograph analysis with high temporal resolution reveals new features of neurofilament transport kinetics". Cytoskeleton. 75 (1): 22–41. doi:10.1002/cm.21411. PMID 28926211.
  15. ↑ Brown A (November 2000). "Slow axonal transport: stop and go traffic in the axon". Nature Reviews. Molecular Cell Biology. 1 (2): 153–6. doi:10.1038/35040102. PMID 11253369.
  16. ↑ Brown A, Wang L, Jung P (September 2005). "Stochastic simulation of neurofilament transport in axons: the "stop-and-go" hypothesis". Molecular Biology of the Cell. 16 (9): 4243–55. doi:10.1091/mbc.E05-02-0141. PMC 1196334. PMID 16000374.
  17. ↑ Jonsson M, Zetterberg H, van Straaten E, Lind K, Syversen S, Edman A, Blennow K, Rosengren L, Pantoni L, Inzitari D, Wallin A (March 2010). "Cerebrospinal fluid biomarkers of white matter lesions - cross-sectional results from the LADIS study". European Journal of Neurology. 17 (3): 377–82. doi:10.1111/j.1468-1331.2009.02808.x. PMID 19845747.
  18. ↑ Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelsø C (November 1996). "Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF". Journal of Neurochemistry. 67 (5): 2013–8. doi:10.1046/j.1471-4159.1996.67052013.x. PMID 8863508.
  19. ↑ Teunissen CE, Iacobaeus E, Khademi M, Brundin L, Norgren N, Koel-Simmelink MJ, Schepens M, Bouwman F, Twaalfhoven HA, Blom HJ, Jakobs C, Dijkstra CD (April 2009). "Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis". Neurology. 72 (15): 1322–9. doi:10.1212/wnl.0b013e3181a0fe3f. PMID 19365053.
  20. ↑ Niemelä V, Landtblom AM, Blennow K, Sundblom J (27 February 2017). "Tau or neurofilament light-Which is the more suitable biomarker for Huntington's disease?". PLOS One. 12 (2): e0172762. doi:10.1371/journal.pone.0172762. PMC 5328385. PMID 28241046.
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