Induction of neuronal death by alpha-synuclein

The molecular and cellular mechanisms underlying neuronal loss in neurodege nerative diseases are unclear. It is generally thought that aggregation of mutated, abnormally modified or abnormally folded proteins leads to the acc umulation of extracellular, intracellular or intranuclear deposits that sev erely compromise cell physiology, leading to the death of the affected neur ons. However, there is growing evidence that neuronal apoptosis in the abse nce of obvious pathological deposits could have a serious impact on the pat hogenesis of neurodegenerative diseases. alpha-Synuclein has been implicate d in aetiology and pathogenesis of certain neurodegenerative diseases, alth ough the precise role of this protein in neurodegeneration is uncertain. Th e normal functions of alpha-synuclein and other members of the synuclein fa mily in the development and function of the nervous system also remain elus ive. Here we show that overexpression of wild-type and mutant forms of alph a-synuclein in cultured neurons, but not the closely related persyn (gamma- synuclein), causes apoptosis. These findings suggest that abnormalities of alpha-synuclein metabolism could lead to the neuronal loss occurring in cer tain forms of neurodegeneration before the formation of characteristic path ological lesions.