A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration

Rebecca San Gil, Dana Pascovici, Juliana Venturato, Heledd Brown-Wright, Prachi Mehta, Lidia Madrid San Martin, Jemma Wu, Wei Luan, Yi Kit Chui, Adekunle T. Bademosi, Shilpa Swaminathan, Serey Naidoo, Britt A. Berning, Amanda L. Wright, Sean S. Keating, Maurice A. Curtis, Richard L. M. Faull, John D. Lee, Shyuan T. Ngo, Albert Lee, Marco Morsch, Roger S. Chung, Emma Scotter, Leszek Lisowski, Mehdi Mirzaei and Adam K. Walker ()
Additional contact information
Rebecca San Gil: The University of Queensland
Dana Pascovici: Insight Stats
Juliana Venturato: The University of Queensland
Heledd Brown-Wright: The University of Queensland
Prachi Mehta: The University of Queensland
Lidia Madrid San Martin: The University of Queensland
Jemma Wu: Macquarie University
Wei Luan: The University of Queensland
Yi Kit Chui: The University of Queensland
Adekunle T. Bademosi: The University of Queensland
Shilpa Swaminathan: The University of Queensland
Serey Naidoo: University of Auckland
Britt A. Berning: The University of Queensland
Amanda L. Wright: The University of Queensland
Sean S. Keating: The University of Queensland
Maurice A. Curtis: University of Auckland
Richard L. M. Faull: University of Auckland
John D. Lee: The University of Queensland, St Lucia
Shyuan T. Ngo: The University of Queensland
Albert Lee: Macquarie Medical School, Macquarie University
Marco Morsch: Macquarie Medical School, Macquarie University
Roger S. Chung: Macquarie Medical School, Macquarie University
Emma Scotter: University of Auckland
Leszek Lisowski: Children’s Medical Research Institute
Mehdi Mirzaei: Macquarie University
Adam K. Walker: The University of Queensland

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map ( https://shiny.rcc.uq.edu.au/TDP-map/ ). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases.

Date: 2024
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DOI: 10.1038/s41467-024-45646-9

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