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
Affiliations
Jasbir Singh Dalal
Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States
Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States
Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States
Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States
Achint Singh
Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States
Truc Thanh Pham
Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States
Pingzhu Zhou
Department of Cardiology, Boston Children’s Hospital, Boston, United States
William T Pu
Department of Cardiology, Boston Children’s Hospital, Boston, United States; Harvard Medical School, Boston, United States
Meghan T Miller
Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland
Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States; Harvard Medical School, Boston, United States
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.
