Virginia Lee

Center for Neurodegenerative Disease Research

University of Pennsylvania

Philadelphia, PA

Unraveling a common thread in neurodegenerative diseases: abnormal TDP-43 protein links Lou Gehrig's disease and frontotemporal dementia

Over the past decade it has become clear that there is significant overlap in the clinical spectrum of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. The identification of TDP-43 as the major disease protein in the pathology of both frontotemporal lobar degeneration with ubiquitin inclusions and amyotrophic lateral sclerosis provides the first molecular link for these diseases. Pathological TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved to generate carboxy-terminal fragments in affected brain regions. The normal nuclear expression of TDP-43 is also reduced leading to the hypothesis that sequestration of TDP-43 in pathological inclusions contributes to disease pathogenesis. Thus, TDP-43 is the newest member of the growing list of neurodegenerative proteinopathies, but unique in that it lacks features of brain amyloidosis.