bafilomycin-a1 and Parkinson-Disease

Topics: 1-Methyl-4-phenylpyridinium; Adenine; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Humans; Macrolides; Mitochondria; Neuroprotective Agents; Parkinson Disease; Reactive Oxygen Species; Valproic Acid

Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson disease (PD), with accumulating evidence that prefibrillar oligomers and protofibrils are the pathogenic species in PD and related synucleinopathies. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a key regulator of mitochondrial biogenesis and cellular energy metabolism, has recently been associated with the pathophysiology of PD. Despite extensive effort on studying the function of PGC-1α in mitochondria, no studies have addressed whether PGC-1α directly influences oligomerization of α-syn or whether α-syn oligomers impact PGC-1α expression.. We tested whether pharmacological or genetic activation of PGC-1α or PGC-11α knockdown could modulate the oligomerization of α-syn in vitro by using an α-syn -fragment complementation assay.. In this study, we found that both PGC-1α reference gene (RG-PGC-1α) and the central nervous system (CNS)-specific PGC-1α (CNS-PGC-1α) are downregulated in human PD brain, in A30P α-syn transgenic animals, and in a cell culture model for α-syn oligomerization. Importantly, downregulation of both RG-PGC-1α and CNS-PGC-1α in cell culture or neurons from RG-PGC-1α-deficient mice leads to a strong induction of α-syn oligomerization and toxicity. In contrast, pharmacological activation or genetic overexpression of RG-PGC-1α reduced α-syn oligomerization and rescued α-syn-mediated toxicity.. Based on our results, we propose that PGC-1α downregulation and α-syn oligomerization form a vicious circle, thereby influencing and/or potentiating each other. Our data indicate that restoration of PGC-1α is a promising approach for development of effective drugs for the treatment of PD and related synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Embryo, Mammalian; Enzyme Inhibitors; Female; Gene Expression Regulation; Glioma; Humans; Macrolides; Male; Mice; Mice, Transgenic; Middle Aged; Neurons; Parkinson Disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Resveratrol; RNA Polymerase II; Stilbenes; Substantia Nigra; TATA-Box Binding Protein; Transcription Factors

Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology. It is considered as a multifactorial disease dependent on environmental and genetic factors. Deregulation in cell degradation has been related with a significant increase in cell damage, becoming a target for studies on the PD etiology. In the present study, we have characterized the parkinsonian toxin 1-methyl-4-phenylpyridinium ion (MPP(+))-induced damage in fibroblasts from Parkinson's patients with the mutation G2019S in leucine-rich repeat kinase 2 protein (LRRK2) and control individuals without this mutation. The results reveal that MPP(+) induces mTOR-dependent autophagy in fibroblasts. Moreover, the effects of caspase-dependent cell death to MPP(+) were higher in cells with the G2019S LRRK2 mutation, which showed basal levels of autophagy due to the G2019S LRRK2 mutation (mTOR-independent). The inhibition of autophagy by 3-methyladenine (3-MA) treatment reduces these sensitivity differences between both cell types, however, the inhibition of autophagosome-lysosome fusion by bafilomycin A1 (Baf A1) increases these differences. This data confirm the importance of the combination of genetic and environmental factors in the PD etiology. Thereby, the sensitivity to the same damage may be different in function of a genetic predisposition, reason why individuals with certain mutations can develop some early-onset diseases, such as individuals with G2019S LRRK2 mutation and PD.

Topics: 1-Methyl-4-phenylpyridinium; Adenine; Autophagy; Case-Control Studies; Caspases; Cells, Cultured; Dose-Response Relationship, Drug; Fibroblasts; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lysosomes; Macrolides; Mutation; Parkinson Disease; Phenotype; Protein Serine-Threonine Kinases; Risk Factors; TOR Serine-Threonine Kinases; Transfection