The aggregation of brain proteins into filamentous lesions is emerging as a common mechanistic theme in sporadic and hereditary neurodegenerative disorders, including Alzheimer disease (AD) and Parkinson disease (PD). For example, in the appropriate clinical setting, numerous telencephalic β-amyloid peptide-rich senile plaques and τ-rich neurofibrillary tangles (NFTs) are diagnostic of AD, while Lewy bodies (LBs) formed by α-synuclein (α-syn) in substantia nigra neurons are signatures of PD. However, filamentous τ lesions are the characteristic neuropathological feature of several other neurodegenerative disorders, referred to as tauopathies, while filamentous α-syn inclusions are hallmarks of another group of diverse neurodegenerative diseases known as synucleinopathies. Moreover, AD and PD commonly cooccur in the same patient, and α-syn is a major component of LBs in an AD-like cognitive disorder known as dementia with LBs and in the LB variant of AD. Further, α-syn positive LBs occur in more than 60% of familial AD brains and in more than 50% of Down syndrome brains, thereby linking mutations in the presenilin and β-amyloid precursor protein genes as well as trisomy 21 to the pathogenesis of α-syn lesions. Although the role of LBs and NFTs in the mechanisms of brain degeneration has been controversial for many years, the recent discovery of pathogenic α-syn gene mutations in familial PD as well as pathogenic τ-gene mutations in familial frontotemporal dementia with parkinsonism linked to chromosome 17 provides unequivocal evidence that abnormal α-syn and τ cause neurodegenerative disease. Clarification of how alterations in α-syn and τ genes and/or proteins lead to the onset/progression of synucleinopathies and tauopathies, respectively, could advance understanding of these disorders and the development of more effective therapies. This presentation reviewed recent insights into the pathobiological features of synucleinopathies and tauopathies that could be exploited for the development of diagnostic biomarkers of these 2 distinct categories of neurodegenerative disease.
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