Recently, mutations of the alpha-synuclein gene were found to cause dominantly inherited Lewy-body
Parkinson's disease (PD) and alpha-synuclein was identified as a major component of the Lewy body.
However, the cause of the common form of PD, with a multifactorial rather than autosomal dominant
inheritance pattern, remains unknown. Alpha-synuclein precipitates slowly and apparently spontaneously at
high concentration in solution and the mutations that cause PD accelerate precipitation. Other dominantly
inherited late-onset or adult-onset dominantly inherited neurodegenerative diseases are associated with
precipitation of proteins. In Alzheimer disease, beta-amyloid and tau abnormalities are present and in prion
disorders, prion proteins are found. In Huntington disease, a disorder with expanded CAG repeats,
huntingtin precipitates occur. In dominantly inherited spinocerebellar ataxias, also expanded CAG repeat
disorders, the corresponding ataxin protein precipitates are found. In multiple system atrophy, alpha-
synuclein precipitates are encountered and in progressive supranuclear palsy, tau precipitates occur. In
familial amyotrophic lateral sclerosis, a group of dominantly inherited disorders, SOD1 precipitates are
found. Most of these disorders can involve the basal ganglia in some way.
Since similar processes seem to affect neurons of adults or older individuals and since a relatively limited
group of proteins seems to be involved, each producing a form of neurodegeneration, it is possible that
certain common features are present that affect this group of proteins. Candidates include a conformational
shift, as in prions, an abnormality of the ubiquitin-proteosome pathway, as seen in PD, an abnormality of a
pathway preventing precipitation (e.g. chaperonins), or potentiation of a pathway promoting precipitation
(e.g. gamma-glutamyl-transpeptidase) or apoptosis. Elucidation of the pathways causing this protein
insolubilisation is the first step towards approaching prevention and reversal in these late-onset
neurodegenerative diseases.