Genetics of Parkinson's disease

Abstract

Over the past few years, several genes for monogenically inherited forms of Parkinson's disease (PD) have been mapped and/or cloned. In a small number of families with autosomal dominant inheritance and typical Lewy-body pathology, mutations have been identified in the gene for alpha-synuclein. Aggregation of this protein in Lewy-bodies may be a crucial step in the molecular pathogenesis of familial and sporadic PD. On the other hand, mutations in the parkin gene cause autosomal recessive parkinsonism of early onset. In this form of PD, nigral degeneration is not accompanied by Lewy-body formation. Parkin-mutations appear to be a common cause of PD in patients with very early onset. Parkin has been implicated in the cellular protein degradation pathways, as it has been shown that it functions as a ubiquitin ligase. The potential importance of this pathway is also highlighted by the finding of a mutation in the gene for ubiquitin C-terminal hydrolase L1 in another small family with PD. Other loci have been mapped to chromosome 2p and 4p, respectively, in a small number of families with dominantly inherited PD, but those genes have not yet been identified. These findings prove that there are several genetically distinct forms of PD that can be caused by mutations in single genes. On the other hand, there is at present no direct evidence that any of these genes have a direct role in the aetiology of the common sporadic form of PD. Epidemiological, case control, and twin studies, although supporting a genetic contribution to the development of PD, all suggest a clear familial clustering only in a minority of cases. It is therefore widely believed that a combination of interacting genetic and environmental causes may be responsible in this majority of PD-cases. However, studies of gene-environment interactions have not yet produced any convincing results. Nevertheless, the elucidation of the molecular sequence of events leading to nigral degeneration in clearly inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.

Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders

“…Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects 1% of the population over 65 [15]. Approximately six million people worldwide have PD.…”

Chromosome 5 and Parkinson disease

“…1 PD is characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as a clinically significant response to treatment with levodopa. 2 Recent studies have consistently found a significant genetic contribution to the risk of PD. Genetic analyses have identified five genes, which when mutated can result in PD.…”

“…Genetic analyses have identified five genes, which when mutated can result in PD. 3 Two of these genes, SNCA and LRRK2, act in an autosomal dominant manner whereas the other three genes, PRKN, PINK1 and DJ1, are autosomal recessive in their mode of action. The majority of families with PD are not segregating a simple Mendelian form of disease.…”

Zinc supplement greatly improves the condition of parkin mutant Drosophila

“…Oxidative stress is considered to be a major factor in the pathogenesis of PD, as evidenced by an elevated content of redox-active iron and lipid peroxides in the diseased brain, impaired mitochondrial function, and alterations in the antioxidant defense mechanisms (Dexter et al, 1989;Jenner and Olanow, 1996;Greene et al, 2003;Pesah et al, 2004). Mutations in six genes, including parkin which encodes an E3 ubiquitin ligase, have been associated with rare, early-onset, familial forms of PD (West and Maidment, 2004;Gasser, 2005;Sang et al, 2007). Interestingly, some alleles of these genes might be susceptibility factors for environmental toxins (Choi et al, 2000;Warner and Schapira, 2003;Bueler, 2009).…”