Enhanced lysosomal activity prevents infection with PrPSc and the seeding activity of α-synuclein & tau prions
Prion diseases are fatal neurodegenerative diseases of humans and other mammals with no current treatment options. Here, we describe the characterization of a novel anti-prion compound, elacridar (GW120918), which has sub-micromolar activity in assays of prion infection, propagation and toxicity. Elacridar acts at an early step in the prion infection process, enhancing degradation of newly formed PrP<sup>Sc</sup>. The lysosome is the likely site of elacridar's anti-prion effects, based on transcriptomic analysis and the use of functional lysosomal probes. Elacridar alters gene expression networks controlling lysosomal sterol and lipid metabolism but, unlike other lysosomotropic drugs, it prominently upregulates genes that control lysosomal pH. Surprisingly, these effects occur independently of TFEB nuclear translocation, suggesting novel regulatory mechanisms. The anti-prion effects of elacridar extend to α-synuclein and tau prions, highlighting lysosomal enhancement as a general strategy for treatment of protein misfolding neurodegenerative diseases.
Authors
- Emily Flaherty
- Glenn C. Telling (ORCID: https://orcid.org/0000-0002-6294-1805)
- Roberto Chiesa (ORCID: https://orcid.org/0000-0002-3842-3733)
- David A. Harris (ORCID: https://orcid.org/0000-0002-6985-5790)
- Robert C.C. Mercer (ORCID: https://orcid.org/0000-0001-6029-511X)
- Jean R. P. Gatdula (ORCID: https://orcid.org/0000-0003-4322-3880)
- Aaron B. Beeler (ORCID: https://orcid.org/0000-0002-2447-0651)
- Janelle S. Vultaggio
- Isabel C. Orbe (ORCID: https://orcid.org/0000-0003-4467-6590)
- Nadia Mirza (ORCID: https://orcid.org/0000-0003-0015-0896)
- Giada Lavigna (ORCID: https://orcid.org/0000-0001-9615-0166)
- Nhat T. T. Le (ORCID: https://orcid.org/0000-0003-0528-8114)
- Joseph P. DeFranco (ORCID: https://orcid.org/0000-0003-3194-2677)
- Jean R. P. Gatdula (ORCID: https://orcid.org/0000-0003-4322-3880)
Institutions
- Boston University (US)
- Mario Negri Institute for Pharmacological Research (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Colorado State University (US)
Publication Details
- Journal
- Journal of Biological Chemistry
- Published
- 2025-12-13
- DOI
- https://doi.org/10.1016/j.jbc.2025.111050
- Citations
- 1
- Primary Topic
- Prion Diseases and Protein Misfolding
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- U.S. Department of Defense
- National Institutes of Health
- University of North Carolina at Chapel Hill
- National Institute of Mental Health