Florent Laferrière et al. in Nature Neuroscience

TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates. Laferrière F , Bezard E Picotti P Lashley T Polymenidou M et al.  Nat Neurosci. 2019 Jan;22(1):65-77. doi: 10.1038/s41593-018-0294-y. Epub 2018 Dec 17.

Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. Laboratoire d’Erwan Bézard


Dans la maladie de Charcot (amyotrophic lateral sclerosis, ALS) ou plusieurs types de maladie de Pick (frontotemporal dementia, FTD), des assemblages pathologiques de protéines distincts ont été identifiés, ayant des propriétés neurotoxiques différentes. Ces pièces manquaient au puzzle…
Qui a tué ces neurones ? Portrait-robot des suspects : Dans la maladie de Charcot (amyotrophic lateral sclerosis, ALS) ou plusieurs types de maladie de Pick (frontotemporal dementia, FTD), des assemblages pathologiques de protéines distincts ont été identifiés, ayant des propriétés neurotoxiques différentes. Ces pièces manquaient au puzzle…

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.

More details in french (link at the top right)

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04/02/19