title: Treating SCA1 Mice with Water-Soluble Compounds to Non-Specifically Boost Mitochondrial Function.
abstract: Mitochondrial dysfunction plays a significant role in the aging process and in neurodegenerative diseases including several hereditary spinocerebellar ataxias and other movement disorders marked by progressive degeneration of the cerebellum. The goal of this protocol is to assess mitochondrial dysfunction in Spinocerebellar ataxia type 1 (SCA1) and assess the efficacy of pharmacological targeting of metabolic respiration via the water-soluble compound succinic acid to slow disease progression. This approach is applicable to other cerebellar diseases and can be adapted to a host of water-soluble therapies. Ex vivo analysis of mitochondrial respiration is used to detect and quantify disease-related changes in mitochondrial function. With genetic evidence (unpublished data) and proteomic evidence of mitochondrial dysfunction in the SCA1 mouse model, we evaluate the efficacy of treatment with the water-soluble metabolic booster succinic acid by dissolving this compound directly into the home cage drinking water. The ability of the drug to pass the blood brain barrier can be deduced using high performance liquid chromatography (HPLC). The efficacy of these compounds can then be tested using multiple behavioral paradigms including the accelerating rotarod, balance beam test and footprint analysis. Cytoarchitectural integrity of the cerebellum can be assessed using immunofluorescence assays that detect Purkinje cell nuclei and Purkinje cell dendrites and soma. These methods are robust techniques for determining mitochondrial dysfunction and the efficacy of treatment with water-soluble compounds in cerebellar neurodegenerative disease.
authors.affiliation: Neuroscience Program, Skidmore College.
authors.forename: Austin
authors.initials: A
authors.lastname: Ferro
authors.affiliation: Neuroscience Program, Skidmore College.
authors.forename: Emily
authors.initials: E
authors.lastname: Carbone
authors.affiliation: Neuroscience Program, Skidmore College.
authors.forename: Evan
authors.initials: E
authors.lastname: Marzouk
authors.affiliation: Chemistry Department, Skidmore College.
authors.forename: Asher
authors.initials: A
authors.lastname: Siegel
authors.affiliation: Neuroscience Program, Skidmore College.
authors.forename: Donna
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: Neuroscience Program, Skidmore College.
authors.forename: Kailen
authors.initials: K
authors.lastname: Polley
authors.affiliation: Neuroscience Program, Skidmore College.
authors.forename: Jessilyn
authors.initials: J
authors.lastname: Hartman
authors.affiliation: Chemistry Department, Skidmore College.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Frederick
authors.affiliation: Health and Exercise Science Department, Skidmore College.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ives
authors.affiliation: Neuroscience Program, Skidmore College; slagalwa@skidmore.edu.
authors.forename: Sarita
authors.initials: S
authors.lastname: Lagalwar
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D003712:Dendrites / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique / Q000379:methods; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects / Q000473:pathology; D012995:Solubility; D020754:Spinocerebellar Ataxias / Q000188:drug therapy* / Q000503:physiopathology*; D019802:Succinic Acid / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
chemical_list: D014867:Water; D019802:Succinic Acid