Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson’s disease model

作者：Chunni Zhu, Tina Bilousova, Samantha Focht, Michael Jun, Chris Jean Elias, Mikhail Melnik, Sujyoti Chandra, Jesus Campagna, Whitaker Cohn, Asa Hatami, Patricia Spilman, Karen H. Gylys, Varghese John · 发表于：Molecular Brain · 年份：2021 · DOI：10.1186/s13041-021-00776-9 · 被引用次数：30 · 研究领域：Extracellular vesicles in disease、Sphingolipid Metabolism and Signaling、Amyotrophic Lateral Sclerosis Research

AIM: We have previously reported that cambinol (DDL-112), a known inhibitor of neutral sphingomyelinase-2 (nSMase2), suppressed extracellular vesicle (EV)/exosome production in vitro in a cell model and reduced tau seed propagation. The enzyme nSMase2 is involved in the production of exosomes carrying proteopathic seeds and could contribute to cell-to-cell transmission of pathological protein aggregates implicated in neurodegenerative diseases such as Parkinson's disease (PD). Here, we performed in vivo studies to determine if DDL-112 can reduce brain EV/exosome production and proteopathic alpha synuclein (αSyn) spread in a PD mouse model. METHODS: The acute effects of single-dose treatment with DDL-112 on interleukin-1β-induced extracellular vesicle (EV) release in brain tissue of Thy1-αSyn PD model mice and chronic effects of 5 week DDL-112 treatment on behavioral/motor function and proteinase K-resistant αSyn aggregates in the PD model were determined. RESULTS/DISCUSSION: In the acute study, pre-treatment with DDL-112 reduced EV/exosome biogenesis and in the chronic study, treatment with DDL-112 was associated with a reduction in αSyn aggregates in the substantia nigra and improvement in motor function. Inhibition of nSMase2 thus offers a new approach to therapeutic development for neurodegenerative diseases with the potential to reduce the spread of disease-specific proteopathic proteins.