Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

Autor:	Prudencio M; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Humphrey J; Ronald M. Loeb Center for Alzheimer's Disease, Nash Family Department of Neuroscience and Friedman Brain Institute, and.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Pickles S; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Brown AL; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom., Hill SE; National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA., Kachergus JM; Department of Cancer Biology, and., Shi J; Department of Cancer Biology, and., Heckman MG; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida, USA., Spiegel MR; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida, USA., Cook C; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Song Y; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA., Yue M; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA., Daughrity LM; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA., Carlomagno Y; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Jansen-West K; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA., de Castro CF; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA., DeTure M; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Koga S; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Wang YC; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Sivakumar P; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom., Bodo C; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom., Candalija A; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom., Talbot K; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom., Selvaraj BT; UK Dementia Research Institute and Euan MacDonald Centre for Motor Neurone Disease (MND) Research, The University of Edinburgh, United Kingdom., Burr K; UK Dementia Research Institute and Euan MacDonald Centre for Motor Neurone Disease (MND) Research, The University of Edinburgh, United Kingdom., Chandran S; UK Dementia Research Institute and Euan MacDonald Centre for Motor Neurone Disease (MND) Research, The University of Edinburgh, United Kingdom., Newcombe J; NeuroResource, Department of Neuroinflammation., Lashley T; Department of Neurodegenerative Disease, and.; Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, United Kingdom., Hubbard I; Center for Genomics of Neurodegenerative Disease, and., Catalano D; Center for Genomics of Neurodegenerative Disease, and., Kim D; Center for Genomics of Neurodegenerative Disease, and., Propp N; Center for Genomics of Neurodegenerative Disease, and., Fennessey S; New York Genome Center (NYGC), New York, New York, USA., Fagegaltier D; Center for Genomics of Neurodegenerative Disease, and., Phatnani H; Center for Genomics of Neurodegenerative Disease, and., Secrier M; University College London Genetics Institute, London, United Kingdom., Fisher EM; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom., Oskarsson B; Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA., van Blitterswijk M; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Rademakers R; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Graff-Radford NR; Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA., Boeve BF; Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA., Knopman DS; Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA., Petersen RC; Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA., Josephs KA; Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA., Thompson EA; Department of Cancer Biology, and., Raj T; Ronald M. Loeb Center for Alzheimer's Disease, Nash Family Department of Neuroscience and Friedman Brain Institute, and.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Ward M; National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA., Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Gendron TF; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA., Fratta P; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom., Petrucelli L; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2020 Nov 02; Vol. 130 (11), pp. 6080-6092.
DOI:	10.1172/JCI139741
Abstrakt:	No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.
Databáze:	MEDLINE
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