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Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

Proceedings of the National Academy of Sciences - PNAS, 2014-03, Vol.111 (9), p.3620-3625 [Tạp chí có phản biện]

copyright © 1993–2008 National Academy of Sciences of the United States of America ;Copyright National Academy of Sciences Mar 4, 2014 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1312245111 ;PMID: 24550511

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Nhan đề:
Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms
Tác giả: Grad, Leslie I. ; Yerbury, Justin J. ; Turner, Bradley J. ; Guest, William C. ; Pokrishevsky, Edward ; O'Neill, Megan A. ; Yanai, Anat ; Silverman, Judith M. ; Zeineddine, Rafaa ; Corcoran, Lisa ; Kumita, Janet R. ; Luheshi, Leila M. ; Yousefi, Masoud ; Coleman, Bradley M. ; Hill, Andrew F. ; Plotkin, Steven S. ; Mackenzie, Ian R. ; Cashman, Neil R.
Chủ đề: Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - metabolism ; Amyotrophic Lateral Sclerosis - physiopathology ; Animals ; Antibodies ; Biological Sciences ; Cell aggregates ; Cell Line ; Cell lines ; Cellular biology ; Electrophoresis, Polyacrylamide Gel ; Exosomes ; Exosomes - metabolism ; Gene expression ; HEK293 cells ; Humans ; Mice ; Microscopy, Electron ; Mutation ; Neurodegenerative diseases ; Neurons ; Neuropsychology ; Pinocytosis - physiology ; Protein Folding ; RNA Interference ; RNA, Small Interfering - genetics ; Rodents ; Spinal cord ; Superoxide Dismutase - chemistry ; Superoxide Dismutase - metabolism ; Superoxides
Là 1 phần của: Proceedings of the National Academy of Sciences - PNAS, 2014-03, Vol.111 (9), p.3620-3625
Mô tả: Amyotrophic lateral sclerosis (ALS) is predominantly sporadic, but associated with heritable genetic mutations in 5–10% of cases, including those in Cu/Zn superoxide dismutase (SOD1). We previously showed that misfolding of SOD1 can be transmitted to endogenous human wild-type SOD1 (HuWtSOD1) in an intracellular compartment. Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWtSOD1 propagation has been established, misfolding of HuWtSOD1 can be efficiently and repeatedly propagated between HEK293 cell cultures via conditioned media over multiple passages, and to cultured mouse primary spinal cord cells transgenically expressing HuWtSOD1, but not to cells derived from nontransgenic littermates. Conditioned media transmission of HuWtSOD1 misfolding in HEK293 cells is blocked by HuWtSOD1 siRNA knockdown, consistent with human SOD1 being a substrate for conversion, and attenuated by ultracentrifugation or incubation with SOD1 misfolding-specific antibodies, indicating a relatively massive transmission particle which possesses antibody-accessible SOD1. Finally, misfolded and protease-sensitive HuWtSOD1 comprises up to 4% of total SOD1 in spinal cords of patients with sporadic ALS (SALS). Propagation of HuWtSOD1 misfolding, and its subsequent cell-to-cell transmission, is thus a candidate process for the molecular pathogenesis of SALS, which may provide novel treatment and biomarker targets for this devastating disease.
Nơi xuất bản: United States: National Academy of Sciences
Ngôn ngữ: English
Số nhận dạng: ISSN: 0027-8424
EISSN: 1091-6490
DOI: 10.1073/pnas.1312245111
PMID: 24550511
Nguồn: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
PubMed Central

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Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

copyright © 1993–2008 National Academy of Sciences of the United States of America ;Copyright National Academy of Sciences Mar 4, 2014 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1312245111 ;PMID: 24550511

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