A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α‐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 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 desaturase (SCD) inhibitor (“5b”) that prevented αS‐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 αS (WT) or an amplified familial PD αS 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 αS hyperphosphorylation in E46K‐expressing human neurons, in 3K neural cultures, and in both WT and 3K αS mice. 5b prevented subtle gait deficits in WT αS mice and the PD‐like resting tremor and progressive motor decline of 3K αS mice. 5b also increased αS 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 α‐synucleinopathies. ANN NEUROL 2021;89:74–90

Therapeutic genetic variation revealed in diverse Hsp104 homologs

“…These yeast models have proven to be powerful platforms that have enabled the discovery of several important genetic and small-molecule modifiers of disease protein aggregation and toxicity. Importantly, these modifiers have translated to more complex model systems including worm, fly, mouse, and neuronal models of neurodegenerative disease ( Armakola et al, 2012 ; Barmada et al, 2015 ; Becker et al, 2017 ; Caraveo et al, 2014 ; Caraveo et al, 2017 ; Chung et al, 2013 ; Cooper et al, 2006 ; Dhungel et al, 2015 ; Elden et al, 2010 ; Fanning et al, 2019 ; Gitler et al, 2009 ; Jackrel et al, 2014 ; Jackson et al, 2015 ; Ju et al, 2011 ; Khurana et al, 2017 ; Kim et al, 2014a ; Nuber et al, 2020 ; Su et al, 2010 ; Tardiff et al, 2013 ; Tardiff et al, 2012 ; Vincent et al, 2018 ). Indeed, potential therapeutics for ALS (e.g.…”

Stearoyl-CoA Desaturase-2 in Murine Development, Metabolism, and Disease

“…Recently, transgenic mice that expressed a PD-associated form of αS were treated with SCD inhibitor by oral administration and were characterized [ 65 ]. Inhibition of SCD protected these mice from gait defects, resting tremor, and progressive motor decline; however, they also exhibited hair loss and dry eyes [ 65 ].…”

“…Recently, transgenic mice that expressed a PD-associated form of αS were treated with SCD inhibitor by oral administration and were characterized [ 65 ]. Inhibition of SCD protected these mice from gait defects, resting tremor, and progressive motor decline; however, they also exhibited hair loss and dry eyes [ 65 ]. Mice heterozygous for Scd1 and expressing a PD-associated form of αS displayed less lipid-rich αS aggregates and performed better on rotarod tests [ 65 ].…”

“…Inhibition of SCD protected these mice from gait defects, resting tremor, and progressive motor decline; however, they also exhibited hair loss and dry eyes [ 65 ]. Mice heterozygous for Scd1 and expressing a PD-associated form of αS displayed less lipid-rich αS aggregates and performed better on rotarod tests [ 65 ]. As SCD inhibitors generally target all SCD isoforms and Scd1 haploinsufficiency is effective in reducing PD phenotypes, specifically inhibiting either SCD2 or hSCD5 in the brain may also be a viable method for combating αS-induced neurotoxicity without unwanted side effects.…”

“…Drugs targeting SCD1 have shown promising effects in mice to prevent Parkinson′s disease, blunt weight gain, improve glucose tolerance, promote sebaceous gland atrophy, protect against fatty liver disease, and inhibit cancer cells [ 65 , 72 ]. Despite this, topical and intraperitoneally injected SCD inhibitors produce unwanted side effects, such as dry eyes, partial eye closure, dry skin, and alopecia [ 45 , 65 , 72 , 73 ]. These side effects do not occur in SCD2KO mice, and therefore SCD2 may be a more suitable drug target than SCD1.…”