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

Chunni Zhu; Tina Bilousova; Samantha Focht; Michael Jun; Chris Jean Elias; Mikhail Melnik; Sujyoti Chandra; Jesus Campagna; Whitaker Cohn; Asa Hatami; Patricia Spilman; Karen Hoppens Gylys; Varghese John

doi:10.1186/s13041-021-00776-9

Molecular Brain (Apr 2021)

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

Chunni Zhu,
Tina Bilousova,
Samantha Focht,
Michael Jun,
Chris Jean Elias,
Mikhail Melnik,
Sujyoti Chandra,
Jesus Campagna,
Whitaker Cohn,
Asa Hatami,
Patricia Spilman,
Karen Hoppens Gylys,
Varghese John

Affiliations

Chunni Zhu: Drug Discovery Lab, Department of Neurology, University of California
Tina Bilousova: Drug Discovery Lab, Department of Neurology, University of California
Samantha Focht: Drug Discovery Lab, Department of Neurology, University of California
Michael Jun: Drug Discovery Lab, Department of Neurology, University of California
Chris Jean Elias: Drug Discovery Lab, Department of Neurology, University of California
Mikhail Melnik: Drug Discovery Lab, Department of Neurology, University of California
Sujyoti Chandra: Drug Discovery Lab, Department of Neurology, University of California
Jesus Campagna: Drug Discovery Lab, Department of Neurology, University of California
Whitaker Cohn: Drug Discovery Lab, Department of Neurology, University of California
Asa Hatami: Drug Discovery Lab, Department of Neurology, University of California
Patricia Spilman: Drug Discovery Lab, Department of Neurology, University of California
Karen Hoppens Gylys: School of Nursing, University of California
Varghese John: Drug Discovery Lab, Department of Neurology, University of California

DOI: https://doi.org/10.1186/s13041-021-00776-9
Journal volume & issue: Vol. 14, no. 1
pp. 1 – 8

Abstract

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Abstract 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.

Published in Molecular Brain

ISSN: 1756-6606 (Online)
Publisher: BMC
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry: Neurology. Diseases of the nervous system
Website: https://molecularbrain.biomedcentral.com/

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Abstract

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