Rare genetic mutations shed light on the pathogenesis of Parkinson disease.

Ultimately it would be of great interest to link all the multiple genes and the sporadic causes of PD into a common pathogenic biochemical pathway — much in the same way that, in AD, the metabolism of the amyloid precursor protein has been shown to be central to the degenerative process. Derangements in protein handling seem to be central in the pathogenesis of PD. Aggregation, fibrillation, and proteasom-al dysfunction seem central to the pathogenesis of α-synuclein–induced injury. Mutations in parkin lead to dysfunction in the proteasomal-degradation pathway. It will be of interest to determine whether parkin is involved in the ubiquitination and elimination of proteins whose proteasomal degradation is impaired by derangements in α-synuclein. The major nonglycosylated form of α-synuclein is linked to parkin through their mutual interactions with synphilin-1, and the minor glycosylated α-synuclein species may be directly linked to parkin, providing further evidence for a common biochemical pathway. How the unfolded-protein stress response fits into a common pathway is not clear. Oxidative stress seems to play a prominent role in sporadic PD, and oxidative stress leads to synuclein aggregation and/or proteasomal dysfunction. Recent data suggest that there may be selective derangements in the protea-somal system in the substantia nigra of sporadic PD patients (68). Thus, protein mishandling may be central to the pathogenesis of PD. Another possible common pathogenic mechanism is the disruption of synaptic function, as α-synuclein, synphilin-1, CDCrel-1, and parkin are synaptically enriched proteins, but this awaits further clarification and investigation. How DJ-1 fits into a common pathogenic pathway is not clear, but its potential role in oxidative stress would fit with the “oxidative stress” hypothesis. The fact the DJ-1 is sumoylated, a ubiquitin-like protein modification, suggests that it might be a target of parkin, tying it into the ubiquitin/proteasomal pathway. Only the future can tell whether DJ-1 and the other yet-to-be-identified PD genes will fit into one of these pathways or whether they will reveal new pathways. Surprises are undoubtedly in store as the identification of these genes leads to a better understanding of the pathogenesis of PD.