title: TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation.
abstract: Parkinson disease (PD) is a neurodegenerative disorder pathologically characterized by nigrostriatal dopamine neuron loss and the postmortem presence of Lewy bodies, depositions of insoluble α-synuclein, and other proteins that likely contribute to cellular toxicity and death during the disease. Genetic and biochemical studies have implicated impaired lysosomal and mitochondrial function in the pathogenesis of PD. Transmembrane protein 175 (TMEM175), the lysosomal K+channel, is centered under a major genome-wide association studies peak for PD, making it a potential candidate risk factor for the disease. To address the possibility that variation in TMEM175 could play a role in PD pathogenesis, TMEM175 function was investigated in a neuronal model system. Studies confirmed that TMEM175 deficiency results in unstable lysosomal pH, which led to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome, and decreased mitochondrial respiration. Moreover, TMEM175 deficiency in rat primary neurons resulted in increased susceptibility to exogenous α-synuclein fibrils. Following α-synuclein fibril treatment, neurons deficient in TMEM175 were found to have increased phosphorylated and detergent-insoluble α-synuclein deposits. Taken together, data from these studies suggest that TMEM175 plays a direct and critical role in lysosomal and mitochondrial function and PD pathogenesis and highlight this ion channel as a potential therapeutic target for treating PD.
authors.affiliation: Target and Pathway Biology, Genetics and Pharmacogenomics, Merck Research Laboratories, Merck & Co., Inc., Boston, MA 02115.|Genetics, Genetics and Pharmacogenomics, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jinn
authors.affiliation: Neuroscience, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Drolet
authors.affiliation: Neuroscience, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486.
authors.forename: Paige E
authors.initials: PE
authors.lastname: Cramer
authors.affiliation: Target and Pathway Biology, Genetics and Pharmacogenomics, Merck Research Laboratories, Merck & Co., Inc., Boston, MA 02115.
authors.forename: Andus Hon-Kit
authors.initials: AH
authors.lastname: Wong
authors.affiliation: Neuroscience, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Toolan
authors.affiliation: Neuroscience, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Gretzula
authors.affiliation: Neuroscience, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486.
authors.forename: Bhavya
authors.initials: B
authors.lastname: Voleti
authors.affiliation: Genomic Sciences, Genetics and Pharmacogenomics, Merck Research Laboratories, Merck & Co., Inc., Boston, MA 02115.
authors.forename: Galya
authors.initials: G
authors.lastname: Vassileva
authors.affiliation: Target and Pathway Biology, Genetics and Pharmacogenomics, Merck Research Laboratories, Merck & Co., Inc., Boston, MA 02115.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Disa
authors.affiliation: Target and Pathway Biology, Genetics and Pharmacogenomics, Merck Research Laboratories, Merck & Co., Inc., Boston, MA 02115.
authors.forename: Marija
authors.initials: M
authors.lastname: Tadin-Strapps
authors.affiliation: Genetics, Genetics and Pharmacogenomics, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486; david_stone4@merck.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Stone
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics*; D061251:Primary Cell Culture; D066329:Protein Aggregates / Q000187:drug effects; D051381:Rats; D051844:alpha-Synuclein / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D015221:Potassium Channels; D066329:Protein Aggregates; C000602835:TMEM175 protein, human; D051844:alpha-Synuclein; D005962:Glucosylceramidase
keywords: Parkinson disease; TMEM175; lysosome; mitochondria; α-synuclein