TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates
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 classificati...
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| Vydáno v: | Nature neuroscience Ročník 22; číslo 1; s. 65 - 77 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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Nature Publishing Group
01.01.2019
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| ISSN: | 1097-6256, 1546-1726, 1546-1726 |
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| 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. |
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| AbstractList | 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.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. 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. Using a newly developed biochemical method for aggregated protein extraction, Laferrière and colleagues uncover different neurotoxic types of pathologic TDP-43 assemblies in the brains of subjects with distinct subtypes of frontotemporal dementia. |
| Author | Pérez-Berlanga, Manuela Hock, Eva-Maria Wagner, Ulrich Afroz, Tariq Barmettler, Gery Hruska-Plochan, Marian Ravits, John Bezard, Erwan Picotti, Paola Asi, Yasmine T Lewis, Amanda Isaacs, Adrian M Stahlberg, Henning Lashley, Tammaryn Gilhespy, Larissa Foti, Sandrine C De Giorgi, Francesca Maniecka, Zuzanna Boersema, Paul J Polymenidou, Magdalini Laferrière, Florent Al-Amoudi, Ashraf Ichas, François |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30559480$$D View this record in MEDLINE/PubMed |
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| Snippet | Accumulation of abnormally phosphorylated TDP-43 (pTDP-43) is the main pathology in affected neurons of people with amyotrophic lateral sclerosis (ALS) and... Using a newly developed biochemical method for aggregated protein extraction, Laferrière and colleagues uncover different neurotoxic types of pathologic TDP-43... |
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| SubjectTerms | Aggregates Amyotrophic lateral sclerosis Anatomy Animals Assemblies Brain Brain - metabolism Brain - pathology Brain architecture Degeneration Dementia Disease Progression DNA-Binding Proteins - metabolism Frontotemporal dementia Frontotemporal Lobar Degeneration - metabolism Frontotemporal Lobar Degeneration - pathology HEK293 Cells Heterogeneity Humans Inclusion Bodies - metabolism Inclusion Bodies - pathology Mass Spectrometry Mass spectroscopy Medical research Mice Morphology Motor neurone disease Mutation Neurodegeneration Neurology Neurons - metabolism Neurons - pathology Neuropathology Neurosciences Neurotoxicity Pathology Phosphorylation Physiology Protein Aggregates - physiology Protein seeding Proteins Scientific imaging Semantics |
| Title | TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates |
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