RT Journal Article
SR Electronic
T1 Parkinson's Disease α-Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 41
OP 50
DO 10.1523/JNEUROSCI.4308-05.2006
VO 26
IS 1
A1 Lee J. Martin
A1 Yan Pan
A1 Ann C. Price
A1 Wanda Sterling
A1 Neal G. Copeland
A1 Nancy A. Jenkins
A1 Donald L. Price
A1 Michael K. Lee
YR 2006
UL http://www.jneurosci.org/content/26/1/41.abstract
AB α-Synuclein (α-Syn) is enriched in nerve terminals. Two mutations in the α-Syn gene (Ala53→ Thr and Ala30→ Pro) occur in autosomal dominant familial Parkinson's disease. Mice overexpressing the human A53T mutant α-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 α-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 α-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 humanα-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.