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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
PubMed

Insights

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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