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The Journal of Neuroscience, August 13, 2008, 28(33):8189-8198; doi:10.1523/JNEUROSCI.2218-08.2008

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Neurobiology of Disease
Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies

Lynn Bedford,¹ David Hay,¹ Anny Devoy,¹ Simon Paine,¹ Des G. Powe,² Rashmi Seth,² Trevor Gray,² Ian Topham,¹ Kevin Fone,¹ Nooshin Rezvani,¹ Maureen Mee,¹ Tim Soane,¹ Robert Layfield,¹ Paul W. Sheppard,³ Ted Ebendal,⁴ Dmitry Usoskin,⁵ James Lowe,^2 * and R. John Mayer^1 *

¹School of Biomedical Sciences and ²School of Molecular Medical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom, ³BIOMOL International L.P., Exeter EX2 8NL, United Kingdom, ⁴Department of Neuroscience, Uppsala University, SE-751 23 Uppsala, Sweden, and ⁵Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-171 77 Stockholm, Sweden

Correspondence should be addressed to R. John Mayer at the above address. Email: john.mayer{at}nottingham.ac.uk

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 -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.

Key words: neuronal death; neuropathology; genetics; transgenic; Parkinson's disease; dementia; proteolysis

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Received May 16, 2008; revised June 10, 2008; accepted June 26, 2008.

Correspondence should be addressed to R. John Mayer at the above address. Email: john.mayer{at}nottingham.ac.uk

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