These main genetic associations are summarized in Table 38-3 and the pathophysiologic significance of the more outstanding ones are discussed below. The former nomenclature of PARK genes followed by numerals has been updated and qualified based on the gene responsible in accord with the approach proposed by the Task Force on the Definition of Parkinson’s Disease (Berg et al). It is clear that many other genes are related to disorders that have parkinsonian features embedded in them, for example, a number of spinocerebellar ataxias, but are not Parkinson disease per se and they are not in this compilation. Several genetic variants have also been tentatively linked to particular nonmotor features of the disease.
As already emphasized, numerous observations have implicated the nuclear and synaptic protein α-synuclein, the main component of Lewy bodies in both the sporadic and inherited forms of Parkinson disease, as well as in Lewy body disease. Synuclein, a normal component of the synapse, exists in a soluble unfolded form, but in high concentrations it aggregates into filaments, which are the main (but not the only) constituent of the Lewy body. Immunostaining techniques disclose additional less-specific proteins, such as ubiquitin and tau within the Lewy bodies. Furthermore, in families with a rare autosomal dominant form of Parkinson disease, several different mutations on chromosome 4 code for an aberrant form of synuclein that decreases its stability and promotes its aggregation (Polymeropoulos et al). A family has also been described in which the cause of Parkinson disease is an extra nonmutant copy of the α-synuclein gene (Singleton et al), comparable to the circumstance or triplication of chromosome 21 in the Alzheimer disease of Down syndrome. Additionally, some cases of familial parkinsonism result from mutations that control the removal of α-synuclein from the cell via proteasomal pathways. Together, these findings indicate that instability or misfolding of α-synuclein or its deficient removal may be a primary defect in the disease. The protofibrillary form of the protein (i.e., a soluble protein in the cytosol) is also toxic to dopaminergic neurons. These processes are accelerated by defects in heat shock proteins that chaperone α-synuclein into and out of the cell. Curiously, Lewy bodies are not found in patients with most of the parkin mutations.
Parkin is a ubiquitin protein ligase that participates in the removal of unnecessary proteins from cells through the proteasomal system (Fig. 38-6). Attachment of parkin and ubiquitin to cytosolic proteins is understood to be an obligatory step in the disposal of proteins by proteasomes. Mutations in the parkin gene lead either to an inadequacy or misfolding of synuclein, resulting in its accumulation, or to the disruption of disposal of proteins in dopamine-producing cells. The importance of the ubiquitination pathway in this disease is further highlighted by the report that parkinsonian features are present in a family with mutations in ubiquitin carboxyterminal hydrolase L1 (Park5, UCHL-1; Table 38-3). Figure 38-6 illustrates these relationships and the processing of synuclein in the cell. It must be emphasized that most of the mechanisms illustrated are speculative or are derived from the molecular study of familial Parkinson disease and therefore may not apply to the sporadic process.