Parkinson's disease (PD) is characterized pathologically by
preferential degeneration of the dopaminergic neurons in the
substantia nigra pars compacta (SNc). Nigral cell death is
accompanied by the accumulation of a wide range of poorly degraded
proteins and the formation of proteinaceous inclusions (Lewy bodies)
in dopaminergic neurons. Mutations in the genes encoding -synuclein
and two enzymes of the ubiquitin-proteasome system, parkin and
ubiquitin C-terminal hydrolase L1, are associated with
neurodegeneration in some familial forms of PD. We now show that, in
comparison to age-matched controls, -subunits (but not -subunits) of
26/20S proteasomes are lost within dopaminergic neurons and 20S
proteasomal enzymatic activities are impaired in the SNc in sporadic
PD. In addition, while the levels of the PA700 proteasome activator
are reduced in the SNc in PD, PA700 expression is increased in other
brain regions such as the frontal cortex and striatum. We also found
that levels of the PA28 proteasome activator are very low to almost
undetectable in the SNc compared to other brain areas in both normal
and PD subjects. These findings suggest that failure of the ubiquitin-
proteasome system to adequately clear unwanted proteins may underlie
vulnerability and degeneration of the SNc in both sporadic and
familial PD.

Kevin St. P. McNaughta, Roger Belizaireb, Ole Isacsonb, Peter Jennerc
and C. Warren Olanowa

a Department of Neurology, Mount Sinai School of Medicine, New York,
New York, 10029
b Neuroregeneration Laboratories, Harvard Medical School and McLean
Hospital, Belmont, Massachusetts, 02478
c Neurodegenerative Disease Research Centre, GKT School of Biomedical
Sciences, King's College, London Bridge, London, SE1 1UL, United
Kingdom