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Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease.
Mov Disord. 2015 Oct; 30(12):1639-47.MD

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+Show Affiliations

Neuroscience Research Australia, Sydney, Australia. School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, Australia.Neuroscience Research Australia, Sydney, Australia.Illawarra Health and Medical Research Institute, Wollongong, Australia. School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.Illawarra Health and Medical Research Institute, Wollongong, Australia. School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.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.Illawarra Health and Medical Research Institute, Wollongong, Australia. School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.Neuroscience Research Australia, Sydney, Australia. School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, Australia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25594542

Citation

Murphy, Karen E., et al. "Lysosomal-associated Membrane Protein 2 Isoforms Are Differentially Affected in Early Parkinson's Disease." Movement Disorders : Official Journal of the Movement Disorder Society, vol. 30, no. 12, 2015, pp. 1639-47.
Murphy KE, Gysbers AM, Abbott SK, et al. Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease. Mov Disord. 2015;30(12):1639-47.
Murphy, K. E., Gysbers, A. M., Abbott, S. K., Spiro, A. S., Furuta, A., Cooper, A., Garner, B., Kabuta, T., & Halliday, G. M. (2015). Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease. Movement Disorders : Official Journal of the Movement Disorder Society, 30(12), 1639-47. https://doi.org/10.1002/mds.26141
Murphy KE, et al. Lysosomal-associated Membrane Protein 2 Isoforms Are Differentially Affected in Early Parkinson's Disease. Mov Disord. 2015;30(12):1639-47. PubMed PMID: 25594542.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease. AU - Murphy,Karen E, AU - Gysbers,Amanda M, AU - Abbott,Sarah K, AU - Spiro,Adena S, AU - Furuta,Akiko, AU - Cooper,Antony, AU - Garner,Brett, AU - Kabuta,Tomohiro, AU - Halliday,Glenda M, Y1 - 2015/01/16/ PY - 2014/08/22/received PY - 2014/10/17/revised PY - 2014/10/20/accepted PY - 2015/1/17/entrez PY - 2015/1/17/pubmed PY - 2016/7/28/medline KW - LAMP2 KW - Parkinson's disease KW - chaperone-mediated autophagy (CMA) KW - nucleic acid autophagy KW - α-synuclein SP - 1639 EP - 47 JF - Movement disorders : official journal of the Movement Disorder Society JO - Mov Disord VL - 30 IS - 12 N2 - 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. SN - 1531-8257 UR - https://www.unboundmedicine.com/medline/citation/25594542/Lysosomal_associated_membrane_protein_2_isoforms_are_differentially_affected_in_early_Parkinson's_disease_ L2 - https://doi.org/10.1002/mds.26141 DB - PRIME DP - Unbound Medicine ER -