Parkinson's disease causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Causes

although most of the cases of Parkinson disease are sporadic and idiopathic, there are some underlying cause for this disease including:

Genetics

There are some evidence showing that there is an association between PD and genetic. This role is higher when Parkinson disease occurs in the individual younger than 50 years old.[1] these studies also demonstrate that if a person has a first degree with PD, the risk of developing PD is 2 to 3 times higher than normal population. Conversely, in 25 to 50 % of PD patients we can find at least one first degree having PD.[2]

Some of specific genes involving in PD are:

Protein misfolding

One of the main underlying cause of PD is mutation in the gene of alpha-synuclein protein which is abundant in the CNS. Its function is thought to be involved in synaptic function and plasticity.[9][10] This mutations lead to unfold alpha-synuclein and aggregation of insoluble protein and neuronal damage. Lewy bodies which are characteristic of PD are mostly build from alpha-synuclein protein.[11]

Defective proteolysis

There are three pathways which control the protein homeostasis in cells: Molecular chaperons, the ubiquitin-proteasome system and autophagy-lysosomal pathway. Alpha synuclein processing is done by all of this three mechanisms and defect in any of them can cause aggregation of this protein and neuronal death.[12][13][14]

Mitochondrial dysfunction

The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an analog of mepridine is found to be associated with PD. The oxidation of this drug produces 1-methyl-4-phenylpyridium which inhibits complex one of mitochondria and result in cell damage. Studies showed that the activity of this complex is decreased in PD patients.[20][21][22]

Oxidative stress

Reactive oxygen species including hydrogen peroxide, superoxide anions and hydroxyradicals are toxic to neurons and cause neuronal damage. They interact with membrane lipids and cause lipid peroxidation which can be seen in substantia nigra of PD patients.[23][24] They can also cause protein misfolding by attacking disulfide isomerase through nitric oxide. Disulfide isomerase is a chaperone preventing the aggregation of proteins.[25]

Iron metabolism

Studies showed that impaired iron metabolism leads to increase amount of iron in substantia nigra of PD patients. One of the underlying etiology of iron accommodation in neuronal cells is the absence of tau protein.[26][27][28]

Immunologic and inflammatory mechanisms

There are some studies supporting the idea of immunologic mechanisms causing PD.[29] In PD patients there is elevated amounts of cyclooxygenase-2 which is the rate limiting enzyme in prostaglandin E2 synthesis.[30] Neuronal cell death can also occur due to infiltration of CD4+ T cells.[31]

References

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