期刊
NATURE NEUROSCIENCE
卷 22, 期 1, 页码 65-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-018-0294-y
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资金
- Swiss National Science Foundation [PP00P3_144862]
- Human Frontier Science Program Career Development Award [CDA-00058/2012]
- UCL/ZNZ Neuroscience Collaboration Grant
- UCL's Wellcome Trust Institutional Strategic Support Fund Investing in Excellent Researchers [105604/Z/14/Z]
- Milton-Safenowitz fellowship from the ALS Association [15-IIP-208, 16-PDF-247]
- University of Zurich
- Alzheimer's Research UK senior fellowship
- Leonard Wolfson Centre for experimental neurology
- European Research Council [648716-C9ND]
- Reta Lila Weston Institute for Neurological Studies
- Progressive Supranuclear Palsy (Europe) Association
- MRC [UKDRI-1006] Funding Source: UKRI
Accumulation of abnormally phosphorylated TDP-43 (pTDP-43) is the main pathology in affected neurons of people with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Morphological diversity and neuroanatomical distribution of pTDP-43 accumulations allowed classification of FTLD cases into at least four subtypes, which are correlated with clinical presentations and genetic causes. To understand the molecular basis of this heterogeneity, we developed SarkoSpin, a new method for biochemical isolation of pathological TDP-43. By combining SarkoSpin with mass spectrometry, we revealed proteins beyond TDP-43 that become abnormally insoluble in a disease subtype-specific manner. We show that pTDP-43 extracted from brain forms stable assemblies of distinct densities and morphologies that are associated with disease subtypes. Importantly, biochemically extracted pTDP-43 assemblies showed differential neurotoxicity and seeding that were correlated with disease duration of FTLD subjects. Our data are consistent with the notion that disease heterogeneity could originate from alternate pathological TDP-43 conformations, which are reminiscent of prion strains.
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