The relevance of a-synuclein for the neurodegenerative process in Lewy body diseases and MSA is now well established. The development of experimental models of a-synucleinopathies has opened the way to the identification of the detailed mechanisms by which the formation of inclusions causes disease. These model systems have also made it possible to identify disease modifiers (enhancers and suppressors) that may well lead to the development of the first mechanism-based therapies for these diseases. At a conceptual level, it will be important to understand whether a-synuclein has a role to play in disorders, such as the autosomal-recessive juvenile forms of parkinsonism caused by mutations in the parkin and DJ-1 genes, or whether there are entirely separate mechanisms by which the dopaminergic nerve cells of the substantia nigra degenerate in PD and in inherited disorders with parkinsonism.
BOX 1: MAJOR RESEARCH ISSUES
The new work has established that a neurodegenerative pathway leading from soluble to insoluble, filamentous a-synuclein is central to Lewy body diseases and multiple system atrophy. The study of familial forms of diseases with filamentous a-synuclein inclusions has revealed that missense mutations in the a-synuclein gene or overexpression of wild-type protein are sufficient to cause neurodegeneration. It appears likely that these genetic defects induce the assembly of a-synuclein into filaments. What causes assembly of a-synuclein in the much more common cases of sporadic disease remains to be discovered. In normal brain, the bio-physically driven propensity of a-synuclein to undergo ordered self-assembly is probably counterbalanced by a number of factors, including the ability of cells to dispose of the protein prior to assembly. Other factors may include the binding of a-synuclein to lipid membranes and its interactions with p- and y-synucleins. Identification of the detailed mechanisms at work constitutes an important area for future research. In particular, we need to know more about the factors that regulate the production of a-synuclein and the mechanisms that ensure its degradation. We need to understand what the toxic a-synuclein species are and how they exert their effects. It appears probable that all familial forms of Lewy body disease are caused by genetic defects that act at the level of the neurodegenerative a-synuclein pathway. It remains to be seen whether they are mechanistically linked to familial forms of parkinsonism that lead to nerve cell loss in the substantia nigra, without formation of Lewy body pathology. The availability of ever better animal models of the a-synucleinopathies opens the way to the identification of genetic and pharmacological modifiers (enhancers and suppressors) of the disease process. This will be essential for a better understanding of the pathogenesis of Lewy body diseases and multiple system atrophy and for the discovery of novel therapeutic avenues.
Was this article helpful?