Format

Send to

Choose Destination
Nat Neurosci. 2019 Jan;22(1):65-77. doi: 10.1038/s41593-018-0294-y. Epub 2018 Dec 17.

TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates.

Author information

1
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
2
Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
3
Institute of Biochemistry, Department of Biology, ETH Zurich (ETHZ), Zurich, Switzerland.
4
Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland.
5
Queen Square Brain Bank for Neurological diseases, Department of Movement Disorders, UCL Institute of Neurology, London, UK.
6
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
7
UK Dementia Research Institute at UCL, UCL Institute of Neurology, London, UK.
8
Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Basel, Switzerland.
9
Department of Neuroscience, University of California, San Diego, La Jolla, CA, USA.
10
INSERM U1084, Laboratoire des Neurosciences Expérimentales et Cliniques, Université de Poitiers, Poitiers, France.
11
Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
12
CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
13
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland. magdalini.polymenidou@imls.uzh.ch.

Abstract

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.

PMID:
30559480
DOI:
10.1038/s41593-018-0294-y

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center