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

Rachel Tesla, Charlotte Guhl, Gordon C. Werthmann, Danielle Dixon, Basar Cenik, Yesu Addepalli, Jue Liang, Daniel M. Fass, Zachary Rosenthal, Stephen J. Haggarty, Noelle S. Williams, Bruce A. Posner, Joseph M. Ready and Joachim Herz ()
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Rachel Tesla: University of Texas Southwestern Medical Center
Charlotte Guhl: Friedrich Schiller University Jena
Gordon C. Werthmann: University of Texas Southwestern Medical Center
Danielle Dixon: University of Texas Southwestern Medical Center
Basar Cenik: University of Texas Southwestern Medical Center
Yesu Addepalli: University of Texas Southwestern Medical Center
Jue Liang: University of Texas Southwestern Medical Center
Daniel M. Fass: Harvard Medical School
Zachary Rosenthal: Massachusetts General Hospital
Stephen J. Haggarty: Harvard Medical School
Noelle S. Williams: University of Texas Southwestern Medical Center
Bruce A. Posner: University of Texas Southwestern Medical Center
Joseph M. Ready: University of Texas Southwestern Medical Center
Joachim Herz: University of Texas Southwestern Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50076-8

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