Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies

Alzheimer's disease and Parkinson's disease are the most common neurodegene rative diseases. They are characterized by the degeneration of selected pop ulations of nerve cells chat develop filamentous inclusions before degenera tion. The neuronal inclusions of Alzheimer's disease are made of the microt ubule-associated protein tau, in a hyperphosphorylated state. Recent work h as shown that the filamentous inclusions of Parkinson's disease are made of the protein alpha-synuclein and that rare, familial forms of Parkinson's d isease are caused by missense mutations in the a-synuclein gene. Besides Pa rkinson's disease, the filamentous inclusions of two additional neurodegene rative diseases, namely dementia with Lewy bodies and multiple system atrop hy have also been found to be made of alpha-synuclein. Abundant filamentous tau inclusions are not limited to Alzheimer's disease. They are the defini ng neuropathological characteristic of froncotemporal dementias such as Pic k's disease, and of progressive supranuclear palsy and corticobasal degener ation. The recent discovery of mutations in the tau gene in familial forms of frontotemporal dementia has provided a direct link between tau dysfuncti on and dementing disease. The new work has established that tauopathies and alpha-synucleinopathies account for most late-onset neurodegenerative dise ases in man. The formation of intracellular filamentous inclusions might be the gain of toxic function that leads to the demise of affected brain cell s.