title: Impairment of mitochondria in adult mouse brain overexpressing predominantly full-length, N-terminally acetylated human α-synuclein.
abstract: While most forms of Parkinson's Disease (PD) are sporadic in nature, a small percentage of PD have genetic causes as first described for dominant, single base pair changes as well as duplication and triplication in the α-synuclein gene. The α-synuclein gene encodes a 140 amino acid residue protein that interacts with a variety of organelles including synaptic vesicles, lysosomes, endoplasmic reticulum/Golgi vesicles and, reported more recently, mitochondria. Here we examined the structural and functional interactions of human α-synuclein with brain mitochondria obtained from an early, pre-manifest mouse model for PD over-expressing human α-synuclein (ASOTg). The membrane potential in ASOTg brain mitochondria was decreased relative to wildtype (WT) mitochondria, while reactive oxygen species (ROS) were elevated in ASOTg brain mitochondria. No selective interaction of human α-synuclein with mitochondrial electron transport complexes cI-cV was detected. Monomeric human α-synuclein plus carboxyl terminally truncated forms were the predominant isoforms detected in ASOTg brain mitochondria by 2-dimensional PAGE (Native/SDS) and immunoblotting. Oligomers or fibrils were not detected with amyloid conformational antibodies. Mass spectrometry of human α-synuclein in both ASOTg brain mitochondria and homogenates from surgically resected human cortex demonstrated that the protein was full-length and postranslationally modified by N-terminal acetylation. Overall the study showed that accumulation of full-length, N-terminally acetylated human α-synuclein was sufficient to disrupt brain mitochondrial function in adult mice.
authors.affiliation: Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Sarafian
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Ryan
authors.forename: Puneet
authors.initials: P
authors.lastname: Souda
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Upendra K
authors.initials: UK
authors.lastname: Kar
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Gary W
authors.initials: GW
authors.lastname: Mathern
authors.forename: Kym F
authors.initials: KF
authors.lastname: Faull
authors.forename: Julian P
authors.initials: JP
authors.lastname: Whitelegge
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Watson
mesh_terms: D000107:Acetylation; D000375:Aging / Q000378:metabolism*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004579:Electron Transport; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D013058:Mass Spectrometry; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012995:Solubility; D013569:Synapses / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000682:Amyloid; D000906:Antibodies; D050505:Mutant Proteins; D020033:Protein Isoforms; C497604:SNCA protein, human; D051844:alpha-Synuclein