Journal Article

DZNE-2026-01157

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Calpain-mediated TBP cleavage disturbs neuronal AMOT-YAP1 signalling.

Incebacak Eltemur, R. D. ; Fath, F. ; Huridou, C. ; Phu, M. D. ; Stoltenow, T. I.DZNE* ; Helm, J.DZNE* ; Pereira Sena, P. ; Casadei, N. ; Velic, A. ; Perera, R. P. ; Macek, B. ; Riess, O. ; Hauser, S.DZNE* ; Nguyen, H. P. ; Philipp, M. ; Weber, J. J.

2026
Springer Nature [London]

This record in other databases:    

Please use a persistent id in citations: doi:10.1038/s41467-026-79055-x

Abstract: The transcription factor TATA-box-binding protein (TBP) plays a crucial role in neurons, as highlighted by its involvement in spinocerebellar ataxia type 17 (SCA17), where pathological polyglutamine expansions disrupt its function. While the molecular pathomechanisms remain unclear, our previous study showed that calcium-activated calpains cleave TBP in SCA17 cell and animal models. Here, we pinpoint a major calpain cleavage site after residue T106, C-terminal to TBP's polyglutamine tract. The resulting polyglutamine-containing N-terminal fragments mislocalise to the cytoplasm and exhibit increased aggregation. Both the N-terminal and the nuclear-localised C-terminal fragments contribute to calpain overactivation. SCA17 cell line-based multi-omics analyses revealed that TBP fragments alter pathways linked to neuronal function and neurodegeneration, identifying AMOT as a key player. Further analyses in SCA17 cell lines, patient-derived fibroblasts and induced neurons as well as in rat and zebrafish models confirmed AMOT's pivotal role in neurons, regulated by TBP and mediated via YAP1-dependent signalling. These findings offer further insights into TBP's neuronal function and suggest broader implications of AMOT for neurodegenerative and neurodevelopmental disorders.

Keyword(s): Animals (MeSH) ; Calpain: metabolism (MeSH) ; Humans (MeSH) ; Neurons: metabolism (MeSH) ; TATA-Box Binding Protein: metabolism (MeSH) ; TATA-Box Binding Protein: genetics (MeSH) ; Signal Transduction (MeSH) ; YAP-Signaling Proteins (MeSH) ; Zebrafish (MeSH) ; Adaptor Proteins, Signal Transducing: metabolism (MeSH) ; Adaptor Proteins, Signal Transducing: genetics (MeSH) ; Rats (MeSH) ; Cell Cycle Proteins: metabolism (MeSH) ; Transcription Factors: metabolism (MeSH) ; Spinocerebellar Ataxias: metabolism (MeSH) ; Spinocerebellar Ataxias: genetics (MeSH) ; Cell Line (MeSH) ; Fibroblasts: metabolism (MeSH) ; Peptides (MeSH) ; Calpain ; TATA-Box Binding Protein ; YAP-Signaling Proteins ; Adaptor Proteins, Signal Transducing ; YAP1 protein, human ; polyglutamine ; Cell Cycle Proteins ; Transcription Factors ; TBP protein, human ; Peptides

---

Contributing Institute(s):

1. Glial Cell Biology (AG Kronenberg-Versteeg)
2. Clinical Neurogenetics (AG Schöls)
3. Advanced cellular models of neurodegeneration (AG Hauser)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
3. 352 - Disease Mechanisms (POF4-352) (POF4-352)

---

Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---