2. Academic Validation
  3. Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency

Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency

  • Nat Commun. 2024 Jul 20;15(1):6125. doi: 10.1038/s41467-024-50076-8.
Rachel Tesla # 1 2,  Charlotte Guhl # 3,  Gordon C Werthmann # 1 2,  Danielle Dixon 1 2,  Basar Cenik 1 2,  Yesu Addepalli 4,  Jue Liang 4,  Daniel M Fass 5,  Zachary Rosenthal 6 7,  Stephen J Haggarty 5,  Noelle S Williams 4,  Bruce A Posner 4,  Joseph M Ready 4,  Joachim Herz 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2 Center for Translational Neurodegeneration Research, Dallas, TX, USA.
  • 3 Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, 07743, Jena, Germany.
  • 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 6 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • 7 Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, USA.
  • 8 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Joachim.Herz@utsouthwestern.edu.
  • 9 Center for Translational Neurodegeneration Research, Dallas, TX, USA. Joachim.Herz@utsouthwestern.edu.
  • 10 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA. Joachim.Herz@utsouthwestern.edu.
  • 11 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Joachim.Herz@utsouthwestern.edu.
  • # Contributed equally.
PMID: 39033178 DOI: 10.1038/s41467-024-50076-8
Abstract

Heterozygous loss-of-function mutations in the GRN gene are a major cause of hereditary frontotemporal dementia. The mechanisms linking frontotemporal dementia pathogenesis to progranulin deficiency are not well understood, and there is currently no treatment. Our strategy to prevent the onset and progression of frontotemporal dementia in patients with GRN mutations is to utilize small molecule positive regulators of GRN expression to boost progranulin levels from the remaining functional GRN allele, thus restoring progranulin levels back to normal within the brain. This work describes a series of blood-brain-barrier-penetrant small molecules which significantly increase progranulin protein levels in human cellular models, correct progranulin protein deficiency in Grn+/- mouse brains, and reverse lysosomal proteome aberrations, a phenotypic hallmark of frontotemporal dementia, more efficiently than the previously described small molecule suberoylanilide hydroxamic acid. These molecules will allow further elucidation of the cellular functions of progranulin and its role in frontotemporal dementia and will also serve as lead structures for further drug development.

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