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

• Published in: Molecular brain Vol. 14; no. 1; p. 70
• Main Authors: Zhu, Chunni, Bilousova, Tina, Focht, Samantha, Jun, Michael, Elias, Chris Jean, Melnik, Mikhail, Chandra, Sujyoti, Campagna, Jesus, Cohn, Whitaker, Hatami, Asa, Spilman, Patricia, Gylys, Karen Hoppens, John, Varghese
• Format: Journal Article
• Language: English
• Published: England BioMed Central 19.04.2021; BMC
• Subjects: Acute effects; Alpha-synuclein; alpha-Synuclein - metabolism; Alzheimer's disease; Animal models; Animals; Behavior; Biosynthesis; Brain - metabolism; Chronic effects; Disease Models, Animal; Endopeptidase K; Enzyme Inhibitors - pharmacology; Exosomes; Exosomes - metabolism; Exosomes - ultrastructure; Extracellular vesicles; IL-1β; Mice, Transgenic; Micro Report; Movement disorders; Naphthalenes - pharmacology; Neurodegenerative diseases; Neutral sphingomyelinase-2; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathology; Protein Aggregates - drug effects; Proteinase; Pyrimidinones - pharmacology; Research methodology; Sirtuins - metabolism; Sphingomyelin phosphodiesterase; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelin Phosphodiesterase - metabolism; Substantia nigra; Sucrose; Synuclein; Tau protein; Extracellular vesicles; Exosomes; Neutral sphingomyelinase-2; Alpha-synuclein; Parkinson’s disease
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/s13041-021-00776-9

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. 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. 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.