FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
| العنوان: | FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade |
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| المؤلفون: | Pierre De Rossi, Johanna Furrer, Tammaryn Lashley, Magdalini Polymenidou, Stefano Scaramuzza, Weijia Zhong, Amanda J Lewis, Ashraf Al-Amoudi, Vera I. Wiersma, Daniel Castaño-Díez, Carolin Böing, Julien Weber, Tomas Demeter, Henning Stahlberg, Manuela Pérez-Berlanga, Zhongning Guo, Marta Di Fabrizio, Carlo Scialo, Laura De Vos, Aurélie Zbinden |
| المساهمون: | University of Zurich, Polymenidou, Magdalini |
| المصدر: | EMBO Reports |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 1303 Biochemistry, Cytoplasmic inclusion, Prions, 610 Medicine & health, Biology, Fibril, Biochemistry, frontotemporal dementia, Article, FTLD‐TDP, 03 medical and health sciences, Dystrophic neurites, 0302 clinical medicine, 1311 Genetics, prion‐like, Ftld tdp, Clinical heterogeneity, mental disorders, 1312 Molecular Biology, Genetics, Directionality, Humans, Molecular Biology of Disease, Translation & Protein Quality, Prion protein, Molecular Biology, 030304 developmental biology, Inclusion Bodies, 0303 health sciences, TDP‐43 strains, Disease progression, nutritional and metabolic diseases, Brain, Articles, 3. Good health, Cell biology, nervous system diseases, TDP‐43, 11493 Department of Quantitative Biomedicine, 030217 neurology & neurosurgery, Neuroscience |
| الوصف: | Morphologically distinct TDP‐43 aggregates occur in clinically different FTLD‐TDP subtypes, yet the mechanism of their emergence and contribution to clinical heterogeneity are poorly understood. Several lines of evidence suggest that pathological TDP‐43 follows a prion‐like cascade, but the molecular determinants of this process remain unknown. We use advanced microscopy techniques to compare the seeding properties of pathological FTLD‐TDP‐A and FTLD‐TDP‐C aggregates. Upon inoculation of patient‐derived aggregates in cells, FTLD‐TDP‐A seeds amplify in a template‐dependent fashion, triggering neoaggregation more efficiently than those extracted from FTLD‐TDP‐C patients, correlating with the respective disease progression rates. Neoaggregates are sequentially phosphorylated with N‐to‐C directionality and with subtype‐specific timelines. The resulting FTLD‐TDP‐A neoaggregates are large and contain densely packed fibrils, reminiscent of the pure compacted fibrils present within cytoplasmic inclusions in postmortem brains. In contrast, FTLD‐TDP‐C dystrophic neurites show less dense fibrils mixed with cellular components, and their respective neoaggregates are small, amorphous protein accumulations. These cellular seeding models replicate aspects of the patient pathological diversity and will be a useful tool in the quest for subtype‐specific therapeutics. Pathological TDP‐43 derived from FTLD patient brains triggers de novo aggregation of physiological TDP‐43 in host cells via a prion‐like cascade. Different subtypes of FTLD‐TDP show distinct organization of TDP‐43 aggregates in patient brains, different seeding potencies, neoaggregate structures and C‐terminal serine phosphorylation timelines. |
| وصف الملف: | 2021_EMBO_Reports_DeRossi_etal.pdf - application/pdf |
| تدمد: | 1469-3178 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c9f02329701a06601ff971cfebc3f4d1Test https://pubmed.ncbi.nlm.nih.gov/34806807Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c9f02329701a06601ff971cfebc3f4d1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14693178 |
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