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

Abstract

Alzheimer'sdisease and Parkinson'sdisease are the most common neurodegenerative diseases. They are characterized by the degeneration of selected populations of nerve cells that develop filamentous inclusions before degeneration. The neuronal inclusions of Alzheimer'sdisease are made of the microtubule–associated protein tau, in a hyperphosphorylated state. Recent work has shown that the filamentous inclusions of Parkinson'sdisease are made of the protein α–synuclein and that rare, familial forms of Parkinson'sdisease are caused by missense mutations in the α–synuclein gene. Besides Parkinson'sdisease, the filamentous inclusions of two additional neurodegenerative diseases, namely dementia with Lewy bodies and multiple system atrophy, have also been found to be made of α–synuclein. Abundant filamentous tau inclusions are not limited to Alzheimer'sdisease. They are the defining neuropathological characteristic of frontotemporal dementias such as Pick'sdisease, and of progressive supranuclear palsy and corticobasal degeneration. The recent discovery of mutations in the tau gene in familial forms of frontotemporal dementia has provided a direct link between tau dysfunction and dementing disease. The new work has established that tauopathies and α–synucleinopathies account for most late–onset neurodegenerative diseases in man. The formation of intracellular filamentous inclusions might be the gain of toxic function that leads to the demise of affected brain cells.