Del Cid-Pellitero, E. | bioRxiv Science

bioRxiv2026

USP15 REGULATES NEUROINFLAMMATION AND DRIVES PATHOGENESIS IN SYNUCLEINOPATHIES

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.

neuroscience↗

bioRxiv2023

A dual hit of α-synuclein internalization and immune challenge leads to formation and maintenance of Lewy body-like inclusions in human dopaminergic neurons

Lewy bodies (LBs), rich in -synuclein, are a hallmark of Parkinsons disease (PD). Understanding their biogenesis is likely to provide insight into the pathophysiology of PD, yet a cellular model for LB formation remains elusive. The realization that the immune challenge is a trigger for neurodegenerative diseases has been a breakthrough in the understanding of PD. Here, iPSC-derived human dopaminergic (DA) neurons from multiple healthy donors were found to form LB-like inclusions following treatment with - synuclein preformed fibrils, but only when coupled to an immune challenge (interferon-gamma or interleukin-1 beta) or when co-cultured with activated microglia. Human cortical neurons derived from the same iPSC lines did not form LB-like inclusions. Exposure to interferon-gamma impairs autophagy in a lysosomal-specific manner in vitro, similar to the disruption of proteostasis pathways that contribute to PD. We find that lysosomal membrane proteins LAMP1 and LAMP2 and transcription factors regulating lysosomal biogenesis and function are downregulated in DA but not cortical neurons. Finally, due to the excellent sample preservation afforded by cells compared to post-mortem PD brain tissue, we conclude that the LB-like inclusions in DA neurons are membrane-bound, suggesting they are not limited to the cytoplasmic compartment. In Brief O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/542776v3_figabs.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1f41855org.highwire.dtl.DTLVardef@69798dorg.highwire.dtl.DTLVardef@ab55bdorg.highwire.dtl.DTLVardef@8a16b8_HPS_FORMAT_FIGEXP M_FIG C_FIG Bayati et al. identify that iPSC-derived dopaminergic neurons undergoing a dual hit treatment of exogenous -synuclein fibrils and proinflammatory cytokines form Lewy body-like inclusions. The dual hit treatment also led to the downregulation of lysosomal proteins. Characterization of inclusions revealed that inclusions were membrane-bound and LC3B-positive, suggesting they are dysfunctional autophagosomes. HighlightsO_LI-synuclein preformed fibril administration coupled with Interferon-gamma exposure leads dopaminergic neurons to form Lewy body-like inclusions C_LIO_LIInclusions are filamentous, membranous, and filled with aberrant organelles C_LIO_LIImpaired autophagic flux and downregulation of TFEB, NRF2, LAMP1, and LAMP2 correlated with inclusion formation C_LIO_LIActivation of NRF2 through the treatment of neurons with the antioxidant perillaldehyde, prevents inclusion formation C_LI

neuroscience↗