title: Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease.
abstract: Lysosomes are the primary catabolic compartment for the degradation of intracellular proteins through autophagy. The presence of abnormal intracellular α-synuclein-positive aggregates in Parkinson's disease (PD) indicates that the degradative capacity of lysosomes is impaired in PD. Specific dysfunction of chaperone-mediated autophagy (CMA) in PD is suggested by reductions in the CMA membrane receptor, lysosomal-associated membrane protein (LAMP) 2A, although whether LAMP2A is the only LAMP2 isoform affected by PD is unknown. Messenger RNA (mRNA) and protein expression of all three LAMP2 isoforms was assessed in brain extracts from regions with and without PD-related increases in α-synuclein in autopsy samples from subjects in the early pathological stage of PD (n = 9), compared to age- and postmortem delay-matched controls (n = 10). In the early stages of PD, mRNA expression of all LAMP2 isoforms was not different from controls, with LAMP2B and LAMP2C protein levels also unchanged in PD. The selective loss of LAMP2A protein directly correlated with the increased levels of α-synuclein and decreased levels of the CMA chaperone heat shock cognate protein 70 in the same PD samples, as well as with the accumulation of cytosolic CMA substrate proteins. Our data show that LAMP2 protein isoforms are differentially affected in the early stages of PD, with LAMP2A selectively reduced in association with increased α-synuclein, and suggests that dysregulation of CMA-mediated protein degradation occurs before substantial α-synuclein aggregation in PD.
authors.affiliation: Neuroscience Research Australia, Sydney, Australia.|School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, Australia.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Murphy
authors.affiliation: Neuroscience Research Australia, Sydney, Australia.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Gysbers
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Abbott
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.
authors.forename: Adena S
authors.initials: AS
authors.lastname: Spiro
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Furuta
authors.affiliation: The Garvan Institute of Medical Research, Sydney, Australia.|St Vincent's Clinical School, Faculty of Medicine, and School of Biotechnology and Biomolecular Sciences, Faculty of Science, The University of New South Wales, Sydney, Australia.
authors.forename: Antony
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong, Australia.|School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Garner
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kabuta
authors.affiliation: Neuroscience Research Australia, Sydney, Australia.|School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D052119:Lysosomal-Associated Membrane Protein 2; D020033:Protein Isoforms; D012333:RNA, Messenger; D051844:alpha-Synuclein; D002784:Cholesterol
keywords: LAMP2; Parkinson's disease; chaperone-mediated autophagy (CMA); nucleic acid autophagy; α-synuclein