Parkinson's Disease

Genetics and Pathogenesis

While the known genes for PD are responsible for only a minority of cases, they have provided extraordinary insight into the molecular pathology of the disease. The known genes are listed in the following table.

Genes for Parkinson's Disease
Locus	Protein or Location	Inheritance	Population
PARK 1	alpha-synuclein mutation	AD	Italian, Greek, German
PARK 2	Parkin	mainly AR	Global
PARK 3	2p13	AD, reduced penetrance	N. European kindred
PARK 4*	alpha-synuclein triplication	AD, reduced penetrance	Isolated families worldwide
PARK 5	UCHL1	AD	German kindred
PARK 6	PINK1	AR	Worldwide
PARK 7	DJ-1	AR	Isolated families worldwide
PARK 8	12p11.2-q13.1	AD, reduced penetrance	Worldwide
PARK 10		Unclear	Icelandic
PARK 13	HtrA2		German

*identification of AS triplication has led to a reclassification of this gene as another instance of PARK 1

AD=autosomal dominant;
AR=autosomal recessive

Proteins of Unknown Function

LRRK2
Leucine-rich repeat kinase 2 (LRRK2) is a protein of unknown function. Mutations in LRRK2 account for 1% to 2% of all cases of PD, and up to 6% of all cases of familial PD. Due to the founder effect, it accounts for up to 40% of PD cases in certain populations.

• L Ozelius, G Senthil, R Saunders-Pullman, E Ohmann, A Deligtisch, M Tagliati, AL Hunt, C Klein, B Henick, SM Hailpern, RB Lipton, J Soto-Valencia, N Risch, SB Bressman. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. NEJM 2006;354:424-425
• S Lesage, A Durr, M Tazir, E Lohmann, AL Leutenegger, S Janin, P Pollak, A Brice, French Parkinson's Disease Study Group. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. NEJM 2006;354:422-423

DJ-1
DJ-1 is a protein of unknown function. Some evidence links it to transcriptional activation.

• J Xu, N Zhong, H Wang, JE Elias, CY Kim, I Woldman, C Pifl, SP Gygi, C Geula, BA Yanker. The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Human Mol Genetics 2005;14:1231-1241

Stress-response Proteins

Alpha-synuclein
Alpha-synuclein (AS) is a ubiquitous neuronal protein that may have a role in protecting nerve terminals from injury and in synaptic vesicle transport or recycling. Despite this potentially protective role, accumulation of AS is a key step in pathogenesis in at least some forms of PD. Overexpression of AS in animal models leads to dose-dependent neurodegeneration, with special susceptibility of dopaminergic cells in the substantia nigra. Triplication of the normal AS gene results in elevated protein levels and development of early-onset PD in several families. In addition, AS promoter variants have been associated with increased risk for PD. AS mutants cause PD in several European families.

The1997 discovery that mutant AS could cause PD led quickly to the discovery that AS was the principal component of Lewy bodies. Lewy bodies are proteinaceous cytoplasmic inclusions found in the brains of PD patients; their exact role is still unknown. The confirmation that triplication of the normal AS gene and resulting elevated protein levels could cause PD greatly strengthened the hypothesis that accumulation of protein is a fundamental event in the pathogenesis of PD.

• S Chandra, G Gallardo, A Fernandez-Chacon, OM Schluter, TC Sudhof. Alpha-synuclein cooperates with CSP-alpha in preventing neurodegeneration. Cell 2005;123:383-396
• M Farrer, J Kachergus, L Forno, S Lincoln, DS Wang, M Hulihan, D Maraganore, K Gwinn-Hardy, Z Wszolek, D Dickson, JW Langston. Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 2004;55:174-179

PINK1
PINK1 is a mitochondrial protein kinase, whose mutation may increase susceptibility to oxidative stress and apoptosis.

HtrA2
HtrA2 is a stress-response serine protease in mitochondria that interacts with PINK1.

• H Plun-Favreau, K Klupsch, N Moisoi, S Gandhi, S Kjaer, D Frith, K Harvey, E Deas, RJ Harvey, N McDonald, NW Wood, M Martins, J Downward. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nature Cell Biology 2007;9:1243-1252

Proteins in the Ubiquitin-proteasome system (UPS)

Parkin
Parkin is a ubiquitin ligase, whose job is to add ubiquitins to proteins destined for degradation by the proteasome. Mutation of parkin impairs its ligation function, leading to protein accumulation within the cell. Homozygous, or compound heterozygous, mutation of parkin leads to early-onset PD, also called autosomal recessive juvenile PD (ARJP). While classified as a recessive disorder, there is some evidence that haploinsufficiency may also occur, such that a heterozygote has increased susceptibility to disease in older individuals. Parkin mutation is the single most common genetic cause of recessive PD, and in one European study was found to be present in 40% of cases with onset before age 40.

• CB Lucking, A Durr, V Bonifati, J Vaughn, G De Michele, T Gasser, B Harhangi, G Meco, P Denefle, NW Wood, Y Agid, A Brice, European Consortium on Genetic Susceptibility in Parkinson's Disease, French Parkinson's Disease Genetics Study Group. Association between early-onset Parkinson's disease and mutations in the parkin gene. NEJM 2000;342:1560-1567

UCHL1
UCHL1 is another member of the ubiquitin proteasome system. Ubiquitin carboxyterminal hydrolase L1 is involved in the metabolism of ubiquitins.

Taken together, the genetic findings suggest that a critical step in the pathogenesis of PD is dysfunction of the UPS. Supporting this conclusion is evidence that specific inhibitors of the UPS cause the neuropathological and motor abnormalities of parkinsonism in model organisms, including rats and mice. How this dysfunction leads to dopaminergic cell death is still not certain, although possible mechanisms include a toxic gain of function of accumulated protein, mitochondrial impairment, and increased oxidative stress. These three mechanisms may also, in the face of other insults, act independently or interdependently to provoke dopaminergic cell death.