Loss of tsc1 in cerebellar purkinje cells induces transcriptional and translation changes in fmrp target transcripts

Jasbir Singh Dalal, Kellen Diamond Winden, Catherine Lourdes Salussolia, Maria Sundberg, Achint Singh, Truc Thanh Pham, Pingzhu Zhou, William T. Pu, Meghan T. Miller, Mustafa Sahin

Research output: Contribution to journalArticlepeer-review

Abstract

Tuberous sclerosis complex (TSC) is a genetic disorder that is associated with multiple neurological manifestations. Previously, we demonstrated that Tsc1 loss in cerebellar Purkinje cells (PCs) can cause altered social behavior in mice. Here, we performed detailed transcriptional and translational analyses of Tsc1-deficient PCs to understand the molecular alterations in these cells. We found that target transcripts of the Fragile X Mental Retardation Protein (FMRP) are reduced in mutant PCs with evidence of increased degradation. Surprisingly, we observed unchanged ribosomal binding for many of these genes using translating ribosome affinity purification. Finally, we found that multiple FMRP targets, including SHANK2, were reduced, suggesting that compensatory increases in ribosomal binding efficiency may be unable to overcome reduced transcript levels. These data further implicate dysfunction of FMRP and its targets in TSC and suggest that treatments aimed at restoring the function of these pathways may be beneficial.

Original languageEnglish (US)
Article numbere67399
JournaleLife
Volume10
DOIs
StatePublished - Jul 2021
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Fingerprint

Dive into the research topics of 'Loss of tsc1 in cerebellar purkinje cells induces transcriptional and translation changes in fmrp target transcripts'. Together they form a unique fingerprint.

Cite this