Activation of Cell Cycle Machinery Mediates Neuronal Cell Death Following Proteasomal Inhibition in a Cellular Model of Parkinson’s Disease

Leonides Stefanis, MD, Ph.D.
Columbia University

The cause of Parkinson’s disease (PD) is still unknown, however three recent genetic links have been described in rare forms of the disease. Mutations were recently identified in some families with dominantly inherited PD in the gene encoding the protein a-synuclein and in the gene encoding the ubiquitin c-terminal hydrolase (UCHL1). Additionally, a rare autosomal recessive form of parkinsonism has been associated with a deletion in a novel gene of unknown function known as parkin. The accumulation of ubiquitinated proteins within Lewy bodies in addition to the genetic data performed suggests that activity of the normal cellular degradation system, and in particular the proteasome, may be dysfunctional in PD. We have found that proteasomal inhibition with the specific, irreversible inhibitor lactacystin can induce pathological features in primary cortical neurons resembling those seen in PD and DLBD, such as the formation of cytoplamic ubiquitinated inclusions and cell death. The proposed studies are aimed at the characterizing the role of cell cycle proteins in neuronal cell death caused by proteasomal inhibition in this cell culture system that we believe may model certain aspects of PD.