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.
journal_name
Nat Neuroscijournal_title
Nature neuroscienceauthors
Laferrière F,Maniecka Z,Pérez-Berlanga M,Hruska-Plochan M,Gilhespy L,Hock EM,Wagner U,Afroz T,Boersema PJ,Barmettler G,Foti SC,Asi YT,Isaacs AM,Al-Amoudi A,Lewis A,Stahlberg H,Ravits J,De Giorgi F,Ichas F,Bezard E,doi
10.1038/s41593-018-0294-ysubject
Has Abstractpub_date
2019-01-01 00:00:00pages
65-77issue
1eissn
1097-6256issn
1546-1726pii
10.1038/s41593-018-0294-yjournal_volume
22pub_type
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