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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Mass spectrometry raw files were uploaded to the ProteomeXchange Consortium via the PRIDE partner repository. Data set identifier: PXD007873. The data that support the findings of this study are available from the corresponding author upon request.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We are grateful to all the subjects and their families for donating tissues for scientific research; this work would not have been possible without their generosity and foresightedness. We thank S. Saberi and M.J. Rodriguez from UCSD for preparing and shipping autopsy material from San Diego to Zurich; A. Käch and the Center for Microscopy and Image Analysis of the University of Zurich for help and technical support in all electron microscopy experiments; H. Leske, K. Frontzek, E. Rushing and A. Aguzzi (Institute of Neuropathology, University Hospital of Zurich) for helpful advice and discussions; J. Luedke and J. Weber for technical help; and S. Sahadevan M.K. and A. Zbinden for critical input on the manuscript. We thank M. Gstaiger (Institute of Molecular Systems Biology, ETH Zurich, Switzerland) for sharing the Flp-In T-REx HEK293 cell line and the pOG44 plasmid. This work was supported by a Swiss National Science Foundation Professorship (PP00P3_144862) and a Human Frontier Science Program Career Development Award (CDA-00058/2012) to M.P. and a UCL/ZNZ Neuroscience Collaboration Grant to M.P and A.M.I funded through UCL’s Wellcome Trust Institutional Strategic Support Fund Investing in Excellent Researchers (105604/Z/14/Z). F.L. and M.H.P. are both recipients of the Milton-Safenowitz fellowship from the ALS Association (15-IIP-208 and 16-PDF-247, respectively). F.L. received a Postdoc Award and Z.M. a Candoc Award (Forschungskredit) from the University of Zurich. T.L. is funded by an Alzheimer’s Research UK senior fellowship. Y.T.A. was supported by the Leonard Wolfson Centre for experimental neurology. A.I. is the recipient of a European Research Council consolidator grant (648716-C9ND). The Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies and the Progressive Supranuclear Palsy (Europe) Association.
Integrated supplementary information
About this article
Nature Neuroscience (2019)