Pharmacological inhibition of nSMase2 reduces brain exosome release and [alpha]-synuclein pathology in a Parkinson's disease model

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 ([alpha]Syn) spread in a PD mouse model. Methods The acute effects of single-dose treatment with DDL-112 on interleukin-1[beta]-induced extracellular vesicle (EV) release in brain tissue of Thy1-[alpha]Syn PD model mice and chronic effects of 5 week DDL-112 treatment on behavioral/motor function and proteinase K-resistant [alpha]Syn 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 [alpha]Syn 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. Keywords: Parkinson's disease, Alpha-synuclein, Extracellular vesicles, Exosomes, Neutral sphingomyelinase-2