TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex
Nicola Alesi1, Damir Khabibullin2, Dean M Rosenthal2
1Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. nalesi@bwh.harvard.edu.
Nature Communications
|January 9, 2024
Summary
Tuberous Sclerosis Complex (TSC) kidney disease is driven by TFEB, a transcription factor. Knocking out TFEB rescues kidney pathology and survival in TSC mouse models, suggesting TFEB as a therapeutic target.
Area of Science:
- Cell Biology
- Genetics
- Nephrology
Background:
- Tuberous Sclerosis Complex (TSC) arises from TSC1/TSC2 mutations, causing mTORC1 hyperactivation and organ lesions.
- TFEB is constitutively active in TSC, suggesting a role in disease pathogenesis.
Purpose of the Study:
- To investigate the role of TFEB in TSC-associated kidney pathology.
- To explore TFEB as a therapeutic target for TSC kidney disease.
Main Methods:
- Generated two mouse models of TSC with primary kidney pathology.
- Utilized TFEB knockout to assess its impact on TSC kidney disease.
- Examined mTORC1 activity, TFEB localization, and lysosomal gene expression.
Main Results:
- TFEB knockout rescued kidney pathology and improved survival in TSC mouse models.
- TFEB knockout normalized increased mTORC1 activity in TSC2-deficient kidneys.
- Rapamycin treatment's benefits in TSC models were TFEB-dependent, normalizing lysosomal gene expression.
Conclusions:
- TFEB is a primary driver of renal disease in Tuberous Sclerosis Complex.
- Targeting TFEB may offer a novel therapeutic strategy for TSC kidney disease.
- Rapamycin's therapeutic effects in TSC are mediated through TFEB-dependent pathways.
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