USP15 REGULATES NEUROINFLAMMATION AND DRIVES PATHOGENESIS IN SYNUCLEINOPATHIES
- 1McGill University
Abstract
Neuroinflammation strongly contributes to the pathogenesis of neurological and neurodegenerative diseases, including Parkinson's disease. We show that ablation of Usp15 in astrocytes and in microglia protects against lethal neuroinflammation in vivo. In a mouse model of synucleinopathy, Usp15 deletion diminishes alpha-syn deposits in the brain, slows disease progression, and increases survival time. The neuroprotective effect of Usp15 is associated with differential expression of inflammatory pathways in situ including interferon stimulated genes. These USP15-dependent effects in vivo are recapitulated in vitro in primary human microglia and astrocytes. We detect high USP15 expression in microglia from Parkinson's patients with strong co-expression with LRRK2 and SNCA. In humans, we detect a strong cis-acting eQTL directing high USP15 expression in CD14+ myeloid cells. The allele driving this eQTL is itself associated with increased disease risk, linking myeloid USP15 expression, elevated USP15 plasma levels in Parkinson's patients, to genetic susceptibility.
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BibTeX
@misc{fodil2026usp15,
title = {{USP15 REGULATES NEUROINFLAMMATION AND DRIVES PATHOGENESIS IN SYNUCLEINOPATHIES}},
author = {N. Fodil and E. Del Cid-Pellitero and V. E.-C. Piscopo and J. Xiao Xuan Luo and M. Wong and J. F. Olivier and A. Alluli and I. Shlaifer and Z. You and C. X.-Q. Chen and N. Aprahamian and Y. Cha and E. Colette and J. Mayo and A. Annett and N. Jabado and C. L. Kleinman and M. N. Kagalwala and J. Ross and M. Lathrop and D. Langlais and T. M. Durcan and E. A. Fon and P. Gros},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.05.749595},
url = {https://www.biorxiv.org/content/10.64898/2026.09.05.749595v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - USP15 REGULATES NEUROINFLAMMATION AND DRIVES PATHOGENESIS IN SYNUCLEINOPATHIES
AU - N. Fodil
AU - E. Del Cid-Pellitero
AU - V. E.-C. Piscopo
AU - J. Xiao Xuan Luo
AU - M. Wong
AU - J. F. Olivier
AU - A. Alluli
AU - I. Shlaifer
AU - Z. You
AU - C. X.-Q. Chen
AU - N. Aprahamian
AU - Y. Cha
AU - E. Colette
AU - J. Mayo
AU - A. Annett
AU - N. Jabado
AU - C. L. Kleinman
AU - M. N. Kagalwala
AU - J. Ross
AU - M. Lathrop
AU - D. Langlais
AU - T. M. Durcan
AU - E. A. Fon
AU - P. Gros
PY - 2026
DA - 2026/09/05
PB - bioRxiv
DO - 10.64898/2026.09.05.749595
UR - https://www.biorxiv.org/content/10.64898/2026.09.05.749595v1
AB - Neuroinflammation strongly contributes to the pathogenesis of neurological and neurodegenerative diseases, including Parkinson's disease. We show that ablation of Usp15 in astrocytes and in microglia protects against lethal neuroinflammation in vivo. In a mouse model of synucleinopathy, Usp15 deletion diminishes alpha-syn deposits in the brain, slows disease progression, and increases survival time. The neuroprotective effect of Usp15 is associated with differential expression of inflammatory pathways in situ including interferon stimulated genes. These USP15-dependent effects in vivo are recapitulated in vitro in primary human microglia and astrocytes. We detect high USP15 expression in microglia from Parkinson's patients with strong co-expression with LRRK2 and SNCA. In humans, we detect a strong cis-acting eQTL directing high USP15 expression in CD14+ myeloid cells. The allele driving this eQTL is itself associated with increased disease risk, linking myeloid USP15 expression, elevated USP15 plasma levels in Parkinson's patients, to genetic susceptibility.
ER -