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

Molecular Brain

Samantha Focht¹  Sujyoti Chandra¹  Mikhail Melnik¹  Varghese John¹  Asa Hatami¹  Chris Jean Elias¹  Patricia Spilman¹  Michael Jun¹  Chunni Zhu¹  Jesus Campagna¹  Whitaker Cohn¹  Tina Bilousova²  Karen Hoppens Gylys³ 

[1] Drug Discovery Lab, Department of Neurology, University of California, 90095, Los Angeles, CA, USA;Drug Discovery Lab, Department of Neurology, University of California, 90095, Los Angeles, CA, USA;School of Nursing, University of California, 90095, Los Angeles, CA, USA;School of Nursing, University of California, 90095, Los Angeles, CA, USA;

关键词: Parkinson’s disease;    Alpha-synuclein;    Extracellular vesicles;    Exosomes;    Neutral sphingomyelinase-2;   

DOI  :  10.1186/s13041-021-00776-9

来源: Springer

【 摘 要 】

AimWe 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.MethodsThe 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/discussionIn 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.

【 授权许可】

CC BY