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…
Neuroinflammation plays a significant role in the progression of neurological and neurodegenerative diseases, such as Parkinson's disease. A study reveals that removing Usp15 in astrocytes and microglia can shield against lethal neuroinflammation in living organisms. In a mouse model of synucleinopathy, the deletion of Usp15 reduces alpha-syn deposits in the brain, decelerates disease advancement, and prolongs lifespan.
The neuroprotective impact of Usp15 is linked to a change in the expression of inflammatory pathways, including interferon-stimulated genes. These Usp15-associated effects in living beings are replicated in a laboratory setting using primary human microglia and astrocytes. Usp15 is found to be highly expressed in microglia from Parkinson's patients, co-existing with LRRK2 and SNCA.
In human subjects, a strong cis-acting eQTL directs high Usp15 expression in CD14+ myeloid cells. The allele responsible for this eQTL is also connected to a higher risk of developing the disease, establishing a relationship between myeloid Usp15 expression, elevated Usp15 plasma levels in Parkinson's patients, and genetic susceptibility.
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