Loss of TDP‐43 oligomerization or RNA binding elicits distinct aggregation patterns

Aggregation of the RNA‐binding protein TAR DNA‐binding protein 43 (TDP‐43) is the key neuropathological feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In physiological conditions, TDP‐43 is predominantly nuclear, for...

Full description

Saved in:
Bibliographic Details
Published in:The EMBO journal 2023-09, Vol.42 (17), p.e111719-n/a
Main Authors: Pérez‐Berlanga, Manuela, Wiersma, Vera I, Zbinden, Aurélie, De Vos, Laura, Wagner, Ulrich, Foglieni, Chiara, Mallona, Izaskun, Betz, Katharina M, Cléry, Antoine, Weber, Julien, Guo, Zhongning, Rigort, Ruben, Rossi, Pierre, Manglunia, Ruchi, Tantardini, Elena, Sahadevan, Sonu, Stach, Oliver, Hruska‐Plochan, Marian, Allain, Frederic H‐T, Paganetti, Paolo, Polymenidou, Magdalini
Format: Article
Language:English
Subjects:
Aggregates
aggregation
Amyotrophic lateral sclerosis
Cell lines
Cellular structure
Cytoplasm
Degeneration
Deoxyribonucleic acid
DNA
Frontotemporal dementia
Inclusion bodies
Inclusions
Liquid phases
LLPS
Localization
Neurodegeneration
Neurodegenerative diseases
Nuclei (cytology)
Oligomerization
Origins
Phase separation
Physiology
Proteasomes
Protein folding
Proteins
Ribonucleic acid
RNA
RNA-binding protein
Stability
TDP‐43
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Aggregation of the RNA‐binding protein TAR DNA‐binding protein 43 (TDP‐43) is the key neuropathological feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In physiological conditions, TDP‐43 is predominantly nuclear, forms oligomers, and is contained in biomolecular condensates assembled by liquid–liquid phase separation (LLPS). In disease, TDP‐43 forms cytoplasmic or intranuclear inclusions. How TDP‐43 transitions from physiological to pathological states remains poorly understood. Using a variety of cellular systems to express structure‐based TDP‐43 variants, including human neurons and cell lines with near‐physiological expression levels, we show that oligomerization and RNA binding govern TDP‐43 stability, splicing functionality, LLPS, and subcellular localization. Importantly, our data reveal that TDP‐43 oligomerization is modulated by RNA binding. By mimicking the impaired proteasomal activity observed in ALS/FTLD patients, we found that monomeric TDP‐43 forms inclusions in the cytoplasm, whereas its RNA binding‐deficient counterpart aggregated in the nucleus. These differentially localized aggregates emerged via distinct pathways: LLPS‐driven aggregation in the nucleus and aggresome‐dependent inclusion formation in the cytoplasm. Therefore, our work unravels the origins of heterogeneous pathological species reminiscent of those occurring in TDP‐43 proteinopathy patients. Synopsis Loss of TDP‐43 oligomerization and RNA binding promotes diverse TDP‐43 pathologies providing insight into the origins of heterogeneous pathological species occurring in human disease. TDP‐43 oligomerization and RNA binding govern its stability, splicing regulation, LLPS, and subcellular localization. TDP‐43 oligomerization is modulated by RNA binding. Monomeric TDP‐43 forms inclusions in the cytoplasm, whereas its RNA binding‐deficient counterpart aggregates in the nucleus. TDP‐43 aggregates emerge via distinct pathways: LLPS‐driven aggregation in the nucleus and aggresome‐dependent inclusion formation in the cytoplasm. Our work unravels the origins of heterogeneous TDP‐43 inclusions reminiscent of those occurring in TDP‐43 proteinopathy patients. Loss of TDP‐43 oligomerization and RNA binding promotes diverse TDP‐43 pathologies providing insights into the origins of heterogeneous pathological species occurring in human disease.
ISSN:0261-4189
1460-2075
DOI:10.15252/embj.2022111719