RT Journal Article
SR Electronic
T1 Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8189
OP 8198
DO 10.1523/JNEUROSCI.2218-08.2008
VO 28
IS 33
A1 Lynn Bedford
A1 David Hay
A1 Anny Devoy
A1 Simon Paine
A1 Des G. Powe
A1 Rashmi Seth
A1 Trevor Gray
A1 Ian Topham
A1 Kevin Fone
A1 Nooshin Rezvani
A1 Maureen Mee
A1 Tim Soane
A1 Robert Layfield
A1 Paul W. Sheppard
A1 Ted Ebendal
A1 Dmitry Usoskin
A1 James Lowe
A1 R. John Mayer
YR 2008
UL http://www.jneurosci.org/content/28/33/8189.abstract
AB Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and α-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.