title: Human A53T α-synuclein causes reversible deficits in mitochondrial function and dynamics in primary mouse cortical neurons.
abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease. A key pathological feature of PD is Lewy bodies, of which the major protein component is α-synuclein (α-syn). Human genetic studies have shown that mutations (A53T, A30P, E46K) and multiplication of the α-syn gene are linked to familial PD. Mice overexpressing the human A53T mutant α-syn gene develop severe movement disorders. However, the molecular mechanisms of α-syn toxicity are not well understood. Recently, mitochondrial dysfunction has been linked with multiple neurodegenerative diseases including Parkinson's disease. Here we investigated whether mitochondrial motility, dynamics and respiratory function are affected in primary neurons from a mouse model expressing the human A53T mutation. We found that mitochondrial motility was selectively inhibited in A53T neurons while transport of other organelles was not affected. In addition, A53T expressing neurons showed impairment in mitochondrial membrane potential and mitochondrial respiratory function. Furthermore, we found that rapamycin, an autophagy inducer, rescued the decreased mitochondrial mobility. Taken together, these data demonstrate that A53T α-syn impairs mitochondrial function and dynamics and the deficit of mitochondrial transport is reversible, providing further understanding of the disease pathogenesis and a potential therapeutic strategy for PD.
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Compound Safety Prediction Group, Pfizer, Inc., Groton, Connecticut, United States of America.
authors.forename: Sashi
authors.initials: S
authors.lastname: Nadanaciva
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Berger
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Katrina
authors.initials: K
authors.lastname: Paumier
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Schwartz
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Kewa
authors.initials: K
authors.lastname: Mou
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Paula
authors.initials: P
authors.lastname: Loos
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Milici
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D010641:Phenotype; D020123:Sirolimus / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D051844:alpha-Synuclein; D020123:Sirolimus