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The Journal of Neuroscience, January 4, 2006, 26(1):41-50; doi:10.1523/JNEUROSCI.4308-05.2006
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Neurobiology of Disease
Parkinson's Disease  -Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death
Lee J. Martin,1,2
Yan Pan,1
Ann C. Price,1
Wanda Sterling,1
Neal G. Copeland,4
Nancy A. Jenkins,4
Donald L. Price,1,2,3 and
Michael K. Lee1
1Department of Pathology, Division of Neuropathology, and Departments of 2Neuroscience and 3Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, and 4Mouse Cancer Genetics Program, National Cancer Institute–Frederick Cancer Center Research and Development Center, Frederick, Maryland 21702
 -Synuclein (-Syn) is enriched in nerve terminals. Two mutations in the -Syn gene (Ala53 Thr and Ala30 Pro) occur in autosomal dominant familial Parkinson's disease. Mice overexpressing the human A53T mutant -Syn develop a severe movement disorder, paralysis, and synucleinopathy, but the mechanisms are not understood. We examined whether transgenic mice expressing human wild-type or familial Parkinson's disease-linked A53T or A30P mutant -syn develop neuronal degeneration and cell death. Mutant mice were examined at early- to mid-stage disease and at near end-stage disease. Age-matched nontransgenic littermates were controls. In A53T mice, neurons in brainstem and spinal cord exhibited large axonal swellings, somal chromatolytic changes, and nuclear condensation. Spheroid eosinophilic Lewy body-like inclusions were present in the cytoplasm of cortical neurons and spinal motor neurons. These inclusions contained human -syn and nitrated synuclein. Motor neurons were depleted ( 75%) in A53T mice but were affected less in A30P mice. Axonal degeneration was present in many regions. Electron microscopy confirmed the cell and axonal degeneration and revealed cytoplasmic inclusions in dendrites and axons. Some inclusions were degenerating mitochondria and were positive for human-syn. Mitochondrial complex IV and V proteins were at control levels, but complex IV activity was reduced significantly in spinal cord. Subsets of neurons in neocortex, brainstem, and spinal cord ventral horn were positive for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, cleaved caspase-3, and p53. Mitochondria in neurons had terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive matrices and p53 at the outer membrane. Thus, A53T mutant mice develop intraneuronal inclusions, mitochondrial DNA damage and degeneration, and apoptotic-like death of neocortical, brainstem, and motor neurons.
Key words: axonopathy; DNA damage; motor neuron disease; neuronal apoptosis; nitrative stress; peroxynitrite; synucleinopathy
Received May 31, 2005;
accepted November 3, 2005.
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