PXD056662

PXD056662 is an original dataset announced via ProteomeXchange.

Title	A novel TTBK2 missense variant causes loss of function and impaired protein phosphorylation: implications for spinocerebellar ataxia type 11
Description	Spinocerebellar ataxia type 11 (SCA11) is a rare form of autosomal dominant cerebellar ataxia, characterized by a relatively slow progression and normal life expectancy. However, it is a highly debilitating disorder. In 2007, SCA11 was genetically linked to TTBK2, which encodes tau tubulin kinase 2 (TTBK2). Since then, only a few families and patients carrying TTBK2 truncating variants have been identified. TTBK2 missense variants were also reported but their pathogenic potential has not been ascertained. TTBK2 has several functions, including the regulation of proteins associated with neurodegeneration, microtubules, and ciliogenesis. Further research is necessary to fully elucidate the precise mechanisms through which TTBK2 variants may cause SCA11. In this study, we investigated the pathogenic mechanisms associated with a novel heterozygous missense variant located in the kinase domain of TTBK2 (NM_173500.4:c.625C>T; p.Leu209Phe), potentially linked to progressive cerebellar ataxia. Through functional studies conducted in a knock-in CRISPR/Cas9 cell model, we associated the variant TTBK2-L209F with reduced TTBK2 protein expression, disturbed cytoskeleton-associated proteins, and deficient kinase activity against TDP-43. Furthermore, our analysis of the phosphoproteome revealed potential impairments in gene regulation, protein degradation, and cytoskeleton-related pathways. Interestingly, altered levels of TGF-β signaling phosphoproteins were also associated with TTBK2-L209F, aligned with findings on other neurodegenerative disorders. These findings open new perspectives and insights into the molecular pathogenesis of SCA11. Moreover, our results underscore the significance of conducting functional studies to validate the impact of TTBK2 missense variants, particularly those located in the kinase domain.
HostingRepository	PRIDE
AnnounceDate	2025-12-22
AnnouncementXML	Submission_2025-12-22_15:28:03.832.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hugo Osorio
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-09 11:34:06	ID requested
⏵ 1	2025-12-22 15:28:04	announced

10.1038/S41598-025-32288-0;

submitter keyword: Spinocerebellar ataxia type 11 (SCA11)

Tau-tubulin kinase 2 (TTBK2)

CRISPR/Cas9

Kinase activity

Phosphoproteomics

Cytoskeleton

Mariana Santos
contact affiliation	1 IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal 2 ICBAS-School of Medicine and Biomedical Sciences, Universidade do Porto, Porto, Portugal
contact email	mariana.graca@ibmc.up.pt
lab head
Hugo Osorio
contact affiliation	i3S - Institute for Research and Innovation in Health, University of Porto
contact email	hosorio@i3s.up.pt
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/12/PXD056662

PRIDE project URI

• PRIDE
  1. PXD056662
     1. Label: PRIDE project
     2. Name: A novel TTBK2 missense variant causes loss of function and impaired protein phosphorylation: implications for spinocerebellar ataxia type 11