Dataset Information

A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in ?-Synuclein Mice.

ABSTRACT:

Objective

Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is ?-synuclein (?S), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing ?S homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl-coenzyme A desaturase (SCD) inhibitor ("5b") that prevented ?S-positive vesicular inclusions and cytotoxicity in cultured human neurons.

Methods

Oral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild-type human ?S (WT) or an amplified familial PD ?S mutation (E35K?+?E46K?+?E61K ["3K"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD-like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD-related lipid changes were quantified in 5b- versus placebo-treated mice. Outcomes were compared to effects of crossing 3K to SCD1^-/- mice.

Results

5b treatment reduced ?S hyperphosphorylation in E46K-expressing human neurons, in 3K neural cultures, and in both WT and 3K ?S mice. 5b prevented subtle gait deficits in WT ?S mice and the PD-like resting tremor and progressive motor decline of 3K ?S mice. 5b also increased ?S tetramers and reduced proteinase K-resistant lipid-rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation.

Interpretation

Prolonged reduction of brain SCD activity prevented PD-like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human ?-synucleinopathies. ANN NEUROL 2021;89:74-90.

SUBMITTER: Nuber S

PROVIDER: S-EPMC7756464 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α-Synuclein Mice.

Nuber Silke S Nam Alice Y AY Rajsombath Molly M MM Cirka Haley H Hronowski Xiaoping X Wang Junmin J Hodgetts Kevin K Kalinichenko Liubov S LS Müller Christian P CP Lambrecht Vera V Winkler Jürgen J Weihofen Andreas A Imberdis Thibaut T Dettmer Ulf U Fanning Saranna S Selkoe Dennis J DJ

Annals of neurology 20201023 1

<h4>Objective</h4>Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is α-synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl-coenzyme A desatu ...[more]

PMID: 32996158

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