Parkinson's disease genetics comes of age

Knowledge about genes in familial parkinsonism helps elucidate idiopathic disease

Parkinson's disease is a neurodegenerative disorder in which loss of dopaminergic cells in the pars compacta of the substantia nigra is recognised to be a central pathological event. Despite several decades of intensive research, however, its cause remains unknown. Although not usually thought of as a hereditary disorder, accumulating evidence suggests a significant genetic component for susceptibility to idiopathic Parkinson's disease. Population based epidemiological studies indicate that the risk of Parkinson's disease is at least doubled in first degree relatives of patientscompared with controls, while hospital based studies suggest a higher risk. 1 2 The lifetime risk in first degree relatives of sporadic cases is estimated to be as high as 17%.3

A molecular genetic approach to the study of Parkinson's disease has been hampered by the relative scarcity of large kindreds with familial Parkinson's disease and the difficulty of obtaining DNA for analysis from more than one generation in this late onset disorder. Despite these difficulties this approach has finally begun to bear fruit. By using as a starting point families in which parkinsonism is clearly inherited as a mendelian trait, three genes for Parkinson's disease have recently been characterised.4^–6

A single amino acid substitution in the gene for α synuclein has recently been shown to segregate with Parkinson's disease in a large Italian-American kindred in whom pathologically typical Parkinson's disease is dominantly inherited over at least five generations.4 The identification of the same mutation in three Greek families and a second mutation in a small German family strengthens the link between α synuclein and Parkinson's disease. 4 7 α Synuclein is one of a family of three small, highly conserved proteins of unknown function which areabundant in neurones with high levels of expression at synaptic terminals, suggesting a role in synaptic plasticity.8 The protein was previously known, havingcome to the attention of researchers as the precursor of the non-amyloid β peptide component of Alzheimer amyloid plaques. Evidence that α synuclein is present at high levels in Lewy body neuronal inclusions, the pathological hallmark of Parkinson's disease, is an intriguing clue which has led to speculation that mutations may be amyloidogenic, causing the protein to aggregate in Lewy bodies and to damage the cell.9

The second of these genes, named parkin, was identified in Japanese families with early onset parkinsonim responsive to levodopa.5 Affected individuals have relatively slowly progressive parkinsonism inherited in autosomal recessive fashion, caused by homozygous deletions in the parkin gene. Parkin is a novel protein with sequence homology to ubiquitin and is expressed in several tissues including brain and substantia nigra. The homology to ubiquitin is particularly interesting as ubiquitin is a component of Lewy bodies, an observation whichis all the more intriguing as these patients differ from those with idiopathic Parkinson's diseasein having no Lewy bodies at necropsy.

The ubiquitin pathway was further implicated in Parkinson's disease with the recent finding, ina single small family with Parkinson's disease, of a heterozygous missense mutation in the gene for a deubiquitinating enzyme named ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which is believed to have a role in the ubiquitin-dependent protein degradation pathway.6 This mutation results in only a 50% reduction in enzyme catalytic activity and its pathogenicity has yet to be unequivocally demonstrated. The mechanisms by which mutations in α synuclein, parkin, and possibly UCH-L1, cause Parkinson's disease remain uncertain at present,and understanding this link will be the next challenge for researchers.

Many patients and their relatives ask their doctors about the genetic basis of Parkinson's disease, an inquiry which seems likely to be made increasingly frequently as news of the recent advances is disseminated. What then is the relevance of these genes to the much commoner, idiopathic form of Parkinson's disease? Systematic screening for α synuclein mutations in patients with both sporadic and familial Parkinson's disease has been largely unrewarding thus far. Studies of UCH-L1 are still awaited, but evidence is accumulating to suggest that parkin mutations may be responsible for a significant proportion of cases of familial Parkinson's disease in patients presentingbefore the age of 58.The possibility that heterozygous carriers of parkin mutations might have increased susceptibility to the disease will also need to be examined.

The genetic contribution to susceptibility to idiopathic Parkinson's disease is likely to be complex. Debate has centred around the existence of one or more interacting disease susceptibility gene which may modify the response to environmental factors—for example, exposure to putative environmental neurotoxins. 10 11 The number and mode of inheritance of any such genes is not yet known. One such genetic susceptibility locus has been mapped to chromosome 2 in a number of small families with Parkinson's disease.12 Attempts to identify susceptibility genes by means of both direct gene sequencing and allelic association studies using both functional and neutral polymorphisms in known genes have not produced consistent results. Candidate genes studied include hepatic detoxification enzymes of the P450 system such as CYP2D6, monoamine oxidase enzymes A and B, dopamine receptor genes, the dopamine transporter, apolipoprotein E, superoxide dismutase, tyrosine hydroxylase, and N-acetyltransferase 2.10

The best hope for unravelling the complex genetic basis of Parkinson's disease may be through screening of the entire genome using DNA markers in affected sibling pairs with Parkinson's disease.Chromosomal regions shared by siblings more often than would be expected by chance may harbour susceptibility genes which could then be cloned. Such studies are large undertakings which are now under way.

Investigation of the genetic basis of familial Parkinson's disease will help elucidate the mechanisms of cell death involved and may be expected to provide insight into the molecular pathogenesis of the much commoner sporadic form of the disease. Although there seems little prospect that these genetic advances will be translated into immediate clinical benefits, they will bring the possibility of prevention or rational treatments a step closer.