Protein Dysfunction in Parkinsonism� Stimulation of Proteolysis as a Treatment for Parkinson’s Disease

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Dr. Kevin McNaught
Harvard Medical School, Massachusetts

Abstract

Parkinson’s disease (PD) is characterized pathologically by degeneration of the dopaminergic nigrostriatal pathway with the appearance of intracytoplasmic Lewy bodies that sequester a range of proteins including ubiquitin and alpha-synuclein. Although the cascade of events leading to neuronal death remains unclear, there is a increasing evidence to suggest that gene defects leading to increased production of mutant proteins and/or impaired proteasomal degradation/clearance of normal and abnormal proteins in these neurons is responsible for their subsequent degeneration. This concept is supported by studies showing that PD related mutations in alpha-synuclein cause this protein to misfold and resist degradation by the proteasome, and both ubiquitin and alpha-synuclein accumulate in neurons when exposed to proteasome inhibitors. These observations lead us to propose that stimulation of proteolysis may prevent neuronal death or rescue degenerating neurons in PD. We now wish to investigate this concept by performing the following studies:

1. Determine the effects of impairment of proteasomal function on protein accumulation, inclusion body formation and cell survival in primary dopaminergic neuronal cultures.

2. Access the ability of activators of proteasome function to increase degradation of endogenous wild-type ubiquitin and alpha-synuclein in primary neuronal cultures. We will also examine the ability of proteasome activators to degrade and clear mutant alpha-synuclein and other proteasome substrates in transfected cell lines.

3. Determine the ability of proteasome activators to slow or prevent development of disease phenotype in transgenic animals expressing mutant alpha-synuclein and other proteasome substrates.

4. Construct expression vectors carrying genes for the endogenous proteasome activators, PA28 and PA700, and access their ability to integrate in host neurons and stimulate proteolysis in cell cultures and in brain in experimental animals.

Progress Report (as of 8/2002)

Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by degeneration of dopamine-containing neurons in the midbrain. In cases of familial PD, mutations that lead to failure of the ubiquitin-proteasome system (UPS) have been identified. These genetic abnormalities do not occur in sporadic PD, but we investigated impairment of the UPS and how it could also contribute to neurodegeneration in PD. We show evidence that failure of the UPS might be a common aetiopathogenic factor underlying the development of familial and sporadic PD (McNaught et al. 2001).

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