␣-Synuclein (␣S) is a protein involved in the cytopathology and genetics of Parkinson disease and is thought to affect mitochondrial complex I activity. Previous studies have shown that mitochondrial toxins and specifically inhibitors of complex I activity enhance ␣S pathogenesis. Here we show that ␣S overexpression specifically inhibits complex I activity in dopaminergic cells and in A53T ␣S transgenic mouse brains. Importantly, our results indicate that the inhibitory effect on complex I activity is not associated with ␣S-related pathology. Specifically, complex I activity measured in purified mitochondria from A53T ␣S transgenic mouse brains was not affected by mouse age; Parkinson disease-like symptoms; levels of ␣S soluble oligomers; levels of insoluble, lipid-associated ␣S; or ␣S intraneuronal depositions in vivo. Likewise, no correlation was found between complex I activity and polyunsaturated fatty acid-induced ␣S depositions in Lewy body-like inclusions in cultured dopaminergic cells. We further show that the effect of ␣S on complex I activity is not due to altered mitochondrial protein levels or affected complex I assembly. Based on the results herein, we suggest that ␣S expression negatively regulates complex I activity as part of its normal, physiological role.Evidence for the involvement of mitochondrial dysfunction in the pathogenesis of Parkinson disease (PD) 2 emerged following the discovery that 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) causes PD-like symptoms in humans (1) and the subsequent findings that its neurotoxic metabolite, the 1-methyl-4-phenylpyridinium ion, inhibits mitochondrial complex I activity (2). Mitochondrial dysfunction represented by inhibition of complex I activity was described in the brain, skeletal muscle, and platelets of a subset of patients with PD (3-5). The finding that DJ-1, Pink1, HTRA2, LRRK2, and Parkin genes that cause familial PD (6 -10) encode mitochondrial proteins has reinforced the link between mitochondrial dysfunction and PD.␣-Synuclein (␣S) is a presynaptic protein critically involved in the cytopathology and genetics of PD (reviewed in Refs. 11-13). In PD and the related human synucleinopathies (14), there is a progressive conversion of the normally highly soluble ␣S protein into insoluble ␤-sheet rich filamentous assemblies, resulting in its intraneuronal deposition into Lewy bodies and Lewy neurites, the cytopathological hallmarks of this group of disorders (15,16).␣S partially localizes to mitochondria in neuronal cells (17) and in ␣S transgenic mice (18), as recently confirmed by others (19 -22). The mitochondrial import of ␣S is energy-dependent and seems to require an outer membrane protein import channel. Once in the mitochondria, ␣S predominantly associates with the inner mitochondrial membrane, where it can apparently interact with and inhibit complex I activity, resulting in increased reactive oxygen species production (21). This effect is enhanced by the pathogenic A53T ␣S mutation (21). Importantly, accumulation of ␣S was also ob...

α-synuclein (α-Syn) is a neuronal protein that accumulates progressively in Parkinson’s disease and related synucleinopathies. Attempting to identify cellular factors that affect α-Syn neuropathology, we previously reported that polyunsaturated fatty acids (PUFAs) promote α-Syn oligomerization and aggregation in cultured cells. We now report that docosahexaenoic acid (DHA) a 22:6 PUFA affects α-Syn oligomerization by activating retinoic X receptor (RXR) and peroxisome proliferator-activated receptor γ2 (PPARγ2). In addition, we show that dietary changes in brain DHA levels affect α-Syn cytopathology in mice transgenic for the Parkinson’s disease-causing A53T mutation in human α-Syn. A diet enriched in docosahexaenoic acid, an activating ligand of RXR, increased the accumulation of soluble and insoluble neuronal α-Syn, neuritic injury and astrocytosis. Conversely, abnormal accumulations of α-Syn and its deleterious effects were significantly attenuated by low dietary docosahexaenoic acid levels. Our results suggest a role for activated RXR/PPARγ 2, obtained by elevated brain polyunsaturated fatty acids levels, in α-Syn neuropathology.

Abstractalpha-Synuclein (αS) is a presynaptic protein implicated in Parkinson's disease (PD). Growing evidence implicates mitochondrial dysfunction, oxidative stress and αS-lipids interactions in the gradual accumulation of αS in pathogenic forms and its deposition in Lewy bodies, the pathological hallmark of PD and related synucleinopathies. The peroxisomal biogenesis disorders (PBD), with Zellweger syndrome serving as the prototype of this group, are characterized by malformed and functionally impaired peroxisomes. Here we utilized the PBD mouse models, Pex2-/-, Pex5-/-and Pex13-/-, to study the potential effects of peroxisomal dysfunction on αS-related pathogenesis. We found increased αS oligomerization and phosphorylation and its increased deposition in cytoplasmic inclusions in these PBD mouse models. Further, we show that αS abnormalities correlate with the altered lipid metabolism and specifically, with accumulation of long chain, n-6 polyunsaturated fatty acids, that occurs in the PBD models.

Alpha Synuclein (α-Syn) is a protein implicated in mechanisms of neuronal degeneration in Parkinson's disease (PD). α-Syn is primarily a neuronal protein, however, its expression is found in various tumors including ovarian, colorectal and melanoma tumors. It has been hypothesized that neurodegeneration may share common mechanisms with oncogenesis. We tested whether α-Syn expression affects tumorigenesis of three types of tumors. Specifically, B16 melanoma, E0771 mammary gland adenocarcinoma and D122 Lewis lung carcinoma. For this aim, we utilized transgenic mice expression the human A53T α-Syn form. We found that the in vivo growth of B16 and E0771 but not D122 was enhanced in the A53T α-Syn mice. The effect on tumorigenesis was not detected in age-matched APP/PS1 mice, modeling Alzheimer's disease (AD), suggesting a specific effect for α-Syn- dependent neurodegeneration. Importantly, transgenic α-Syn expression was detected within the three tumor types. We further show uptake of exogenously added, purified α-Syn, by the cultured tumor cells. In accord, with the affected tumorigenesis in the young A53T α-Syn mice, over- expression of α-Syn in cultured B16 and E0771 cells enhanced proliferation, however, had no effect on the proliferation of D122 cells. Based on these results, we suggest that certain forms of α-Syn may selectively accelerate cellular mechanisms leading to cancer.

ObjectiveWhile evidence for oxidative injury is frequently detected in brains of humans affected by Parkinson's disease (PD) and in relevant animal models, there is uncertainty regarding its cause. We tested the potential role of catalase in the oxidative injury that characterizes PD.MethodsUtilizing brains of A53T α-Syn and ntg mice, and cultured cells, we analyzed catalase activity and expression, and performed biochemical analyses of peroxisomal metabolites.ResultsLower catalase expression and lower activity levels were detected in A53T α-Syn brains and α-Syn-expressing cells. The effect on catalase activity was independent of disease progression, represented by mouse age and α-Syn mutation, suggesting a potential physiological function for α-Syn. Notably, catalase activity and expression were unaffected in brains of mice modeling Alzheimer's disease. Moreover, we found that α-Syn expression downregulate the peroxisome proliferator-activated receptor (PPAR)γ, which controls catalase transcription. Importantly, activation of either PPARγ2, PPARα or retinoic X receptor eliminated the inhibiting effect of α-Syn on catalase activity. In addition, activation of these nuclear receptors enhanced the accumulation of soluble α-Syn oligomers, resulting in a positive association between the degree of soluble α-Syn oligomers and catalase activity. Of note, a comprehensive biochemical analysis of specific peroxisomal metabolites indicated no signs of dysfunction in specific peroxisomal activities in brains of A53T α-Syn mice.InterpretationOur results suggest that α-Syn expression may interfere with the complex and overlapping network of nuclear receptors transcription activation. In result, catalase activity is affected through mechanisms involved in the regulation of soluble α-Syn oligomers.