PXD069405-1

PXD069405 is an original dataset announced via ProteomeXchange.

Title	Phosphoproteomics reveals altered RNA splicing as a major potential driver of pathology in the brain in tuberous sclerosis complex
Description	Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in the genes TSC1 and TSC2, resulting in activation of mechanistic target of rapamycin complex 1 (mTORC1). Neurological manifestations occur in most TSC patients and include epilepsy, autism and intellectual disability. Two types of brain lesions, cortical tubers and subependymal giant cell astrocytomas (SEGAs), cause the majority of neurological manifestations in TSC. We have limited understanding of the molecular changes that occur in tubers and SEGAs and how these contribute to disease pathogenesis. To investigate this, we performed proteomic and phosphoproteomic analysis of TSC patient tuber and SEGA tissue. We were unable to detect mTORC1 activation in tubers, likely due to the small number of cells with complete inactivation of TSC1 or TSC2. By contrast, SEGAs showed evidence of strong mTORC1 activation and large-scale changes in the proteome and phosphoproteome. At the proteomic level, SEGAs exhibited increased expression of ribosomal proteins and activation of a neuroinflammatory response. Phosphoproteomics showed that phosphorylation of a multitude of proteins involved in RNA-metabolism, including mRNA splicing, were increased in SEGAs. Consistent with this, we found evidence of extensive alterations in mRNA transcript splicing in SEGA tissue. Together these data reveal a novel molecular mechanism whereby mTORC1 activation in SEGAs results in mis-regulation of RNA metabolism and mRNA splicing, potentially contributing to the neurological manifestations in TSC.
HostingRepository	PRIDE
AnnounceDate	2026-04-13
AnnouncementXML	Submission_2026-04-13_12:05:49.220.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simeon Mihaylov
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-13 12:42:59	ID requested
⏵ 1	2026-04-13 12:05:49	announced

Dataset with its publication pending

submitter keyword: TMTpro, RNA processing,TSC, human, SEGAs, tubers, mTOR

Sila Konur Ultanir
contact affiliation	Kinases and Brain Development Lab, The Francis Crick Institute, London, UK
contact email	sila.ultanir@crick.ac.uk
lab head
Simeon Mihaylov
contact affiliation	The Francis Crick Institute
contact email	simeon.mihaylov@crick.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD069405
     1. Label: PRIDE project
     2. Name: Phosphoproteomics reveals altered RNA splicing as a major potential driver of pathology in the brain in tuberous sclerosis complex