Parkinson's Disease α-Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death

Abstract

␣-Synuclein (␣-Syn) is enriched in nerve terminals. Two mutations in the ␣-Syn gene (Ala533 Thr and Ala303 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 (ϳ75%) 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 transferasemediated 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.

The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease

“…␣-syn has been implicated in a variety of cellular processes that include regulation of DA homeostasis through regulation of DA transporter activity (8), tyrosine hydroxylase activity (11), or vesicle formation (24). ␣-syn has also been implicated in ER-Golgi trafficking (25), tubulin trafficking (26), interaction with mitochondrial proteins (27), and control of nuclear transcription (12,28). Disruption of any of these processes through expression of a nonphosphorylated mimic could, in principle, lead to cell death.…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…In addition, it was shown that human embryonic kidney cells that overexpress alphaͲsyn, show enhanced susceptibility to cell death and have lower ATP levels compared to control cells [183]. In brainstem neurons of mice that overexpress human A53T mutant alphaͲsyn, there is evidence of degenerating and dysmorphic mitochondria with DNA damage [185]. Furthermore, in both SHͲSY5Y neuroblastoma cells and isolated rat mitochondria, alphaͲsyn seems to induce mitochondrial release of cytochrome c, increased mitochondrial calcium and NO, and oxidative modification of mitochondrial components.…”

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

“…There is limited literature on an association of α-synuclein with mitochondria, although it has been reported that synuclein may be found within degenerating mitochondria [49]. Since low pH fixation appears to mimic synuclein translocation to mitochondria under stress conditions, we used immunoelectron microscopy to examine the subcellular distribution of synuclein in cells stably expressing wild-type α-synuclein fixed under neutral (pH 7.4) or acidic (pH 5.0) conditions.…”