Causes of Parkinson's disease

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Parkinson's disease (PD) is a degenerative disorder of the central nervous system. Most people with PD have idiopathic Parkinson's disease (having no specific known cause). A small proportion of cases, however, can be attributed to known genetic factors. Other factors such as environmental toxins, herbicides, pesticides, and fungicides, have been associated with the risk of developing PD, but no causal relationships have been proven.

Genetic Factors[edit]

PDB rendering of Parkin (ligase)

Traditionally, PD has been considered a non-genetic disorder. However, around 15% of individuals with PD have a first-degree relative who has the disease.[1] At least 5% -15% of cases are known to occur because of a mutation in one of several specific genes, transmitted in either an autosomal-dominant or autosomal-recessive pattern[2][3]

Mutations in specific genes have been conclusively shown to cause PD. Genes which have been implicated in autosomal-dominant PD include PARK1 and PARK4, PARK5, PARK8, PARK11 and GIGYF2 and PARK13 which code for alpha-synuclein(SNCA), UCHL1, leucine-rich repeat kinase 2 (LRRK2 or dardarin)(LRRK2 and Htra2 respectively[2] Genes such as PARK2, PARK, PARK7 and PARK9 which code for parkin (PRKN), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2 respectively have been implicated in the development of autosomal-recessive PD[4][5][6] Furthermore, mutations in genes including those that code for SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD[7] In most cases, people with these mutations will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD.[8] The most extensively studied PD-related genes are SNCA and LRRK2.

SNCA gene[edit]

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies.[2] SNCA is expressed throughout the mammalian brain and enriched in presynaptic nerve terminals. Missense mutations of the gene (in which a single nucleotide is changed), and duplications and triplications of the locus containing it have been found in different groups with familial PD.[2] Missense mutations in SNCA are rare.[2] On the other hand, multiplications of the SNCA locus account for around 2% of familial cases.[2] Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent.[2] Level of alpha-synuclein expression correlates with disease onset and progression, with SNCA gene triplication advancing earlier and faster than duplication.[9]

LRRK2 gene[edit]

The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin was taken from a Basque word for tremor, because this gene was first identified in families from England and the north of Spain.[8] A significant number of autosomal-dominant Parkinson's disease cases are associated with mutations in the LRRK2 gene[3] Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases.[2][8] There are many different mutations described in LRRK2, however unequivocal proof of causation only exists for a small number.[2] Mutations in PINK1, PRKN, and DJ-1 may cause mitochondrial dysfunction, an element of both idiopathic and genetic PD.[9] Of related interest are mutations in the progranulin gene that have been found to cause corticobasal degeneration seen in dementia.[10] This could be relevant in PD cases associated with dementia.[10]

GBA gene[edit]

Mutations in GBA are known to cause Gaucher's disease.[2] Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results.[11] Mendelian genetics are not strictly observed in GBA mutations found in inherited parkinsonism.[12] Incidentally, both gain-of-function and loss-of-function GBA mutations are proposed to contribute to parkinsonism through effects such as increased alpha-synuclein levels.[12]

Genes Underlying Familial Parkinson's Disease[edit]

Genes underlying familial PD
Locus Gene Function Mutations Clinical Presentations Neuropathology Age at onset Inheritance
PARK1/PARK4[13] SNCA[14] (α-synuclein) Unknown synaptic function Duplications Idiopathic PD; some postural tremor; slow progression LBs Mid 20 - 30 Dominant
Triplications PD (Parkinson's Disease); PD with dementia;diffuse LBs disease;aggressive course LBs and Lewy neurites; ± glial inclusions; hippocampal CA2 and CA3 loss Mid 20's - 30's
A53T, A30P E46K[15][16] Idiopathic PD; early on setparkinsonism and diffuse LBs LBs and LNs; ± tau inclusions; amyloid plaques 30 - 60
PARK2[13] Parkin[17] E3 ubiquitin ligase[18] 200+ possible mutations including:[18]

- Inactivating somatic mutations

- Frequent intragenic deletions

Early on set Parkinsonism; slow progression PD variable presence of LBs Juvenile to 40 Recessive
PARK5[13] UCHL1 deubiquitinating enzyme Missense: Ile93Met[19] PD; late on set parkinsonism Unknown; various abnormal protein aggregations 30 - 50 Dominant
PARK6[13] PINK1[20] mitochondrial Ser-Thr Kinase 40+ mutations[20]

-Mostly point mutations

-Deletions on C-terminus Kinase domain

Parkinsonism Unknown 30 - 50 Recessive
PARK7[13] DJ-1[21] oxidative stress response? -10 point mutations including C46A, C53A, C106 & WT regions[21]

- Large deletion in L166P

Early onset Parkinsonism Unknown 20 - 40 Recessive
PARK8[13] LRRK2 (dardarin) unknown protein kinase G2019S most common[22] PD Diffuse LBs; LNs; ± tau inclusions; ± amyloid plaques 40 - 60 Dominant

Overview[edit]

PD is thought to result from a complex interaction between multiple genetic and environmental factors, though rare monogenic forms of the disease do exist. Mutations in 6 genes (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have conclusively been shown to cause familial parkinsonism. In , common variation in 3 genes (MAPT, LRRK2, and SNCA) and loss-of-function mutations in GBA have been well-validated as susceptibility factors for PD. The function of these genes and their contribution to PD pathogenesis remain to be fully elucidated.

Environmental Factors[edit]

Several environmental factors including toxins, pesticides,and metals have been implicated in the development of Parkinson's Disease, although a definitive causal relationship between these toxins and PD has not been determined. Current research has proposed multiple mechanisms through which these toxins may lead to the development of Parkinson's disease.

β-Methylamino-L-Alanine[edit]

beta-Methylamino-L-alanine or BMAA, a non-protein amino acid produced by Cyanobacteria commonly found in contaminated seafood, drinking water and recreational waters might be a major factor in PD.[23] Concrete evidence about the role of BMAA in neuronal dysfunction exhibited in PD has not been found, although current research suggests multiple mechanisms. Studies show that BMAA can be misincorporated into human proteins in place of L-Serine, leading to protein misfolding and abnormal protein aggregation.[24] In this way, BMAA incorporation into human proteins might lead to the formation of Lewy bodies, which develop within nerve cells of the substantia nigra and other brain regions in PD.[24] Increased amounts of L-Serine has shown to inhibit BMAA incorporation into human proteins.[24] Studies have also found that BMAA is an excitotoxin for glutamate receptors, including NMDA, AMPA and kainate receptors.[25] Overstimulation of glutamate receptors leads to increased Reactive oxygen species, resulting in motor neuron injury associated with neurodegenerative diseases such as PD.[25] Another study found that BMAA decreases levels of reduced glutathione, a major antioxidant within the body, which also contributes to neuronal injury.[26]

Organochlorine Pesticides[edit]

Organochlorine pesticides might play a role in the development of PD. One study compared organochlorine compound concentrations in the substantia nigra of PD patients, Cortical Lewy Body Dementia patients, Alzheimer's Disease patients and healthy controls.[27] Concentrations of hexachlorocyclohexane (gammaHCH, lindane) appeared to be higher in the brains of PD patients, compared to Alzheimer's Disease patients and controls, whereas levels of Dieldrin were higher in the PD brain as compared to the AD patients' brains and controls. Concentrations of 1,1'-(2,2-dichloroethenyl diene)-bis(4-chlorobenzene) and polychlorinated biphenyls appeared to be higher in PD brains only when compared to Cortical Lewy Body Dementia.[27] Another study also found increased concentration of Dieldrin in 6 of 20 PD brains compared to none in controls[28] Organochlorine pesticides might act as mitochondrial-poisons, leading to increased oxidative stress within neurons and resulting in dopaminergic neuronal body damage associated with Parkinson's disease.[27]

References[edit]

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