Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders

Abstract

Disturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors.

Keywords: Cellular and molecular dysfunction; Fatty acid metabolism; Neurodegenerative disorders; Stearoyl-CoA desaturases.

Fig. 1

SCD1 is a driver of immune, glia, and neuronal physiology in neurodegenerative disorders such as X-ALD, MS, AD, and PD. In X-linked adrenoleukodystrophy (X-ALD, top left), SCD1 plays a crucial protective role by redirecting saturated to monounsaturated very long–chain fatty acids (VLCFAs), thereby mitigating VLCFA-induced lipotoxicity. However, contrary to X-ALD, heightened activity and abundance of SCD1 drive disease progression in multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). In MS (top right), SCD1-produced monounsaturated FAs (MUFA) destabilize plasma membrane ATP-binding cassette transporter ABCA1 in a PKCδ-dependent manner, leading to intracellular accumulation of highly inflammatory free cholesterol in foamy myelin-containing macrophages and microglia. Moreover, SCD1 acts as a brake on Treg differentiation, exacerbating neuroinflammation by suppressing adipose triglyceride lipase (ATGL)-dependent release of docosahexaenoic acid (DHA) and subsequent peroxisome proliferator-activated receptor γ (PPARγ) activation. In AD (bottom left), disrupted saturated FAs (SFA)/MUFA ratios disrupt ependymal cell function in the subventricular zone (SVZ), impairing neural stem cell (NSCs) physiology (e.g. proliferative deficits), a hallmark of AD. Additionally, SCD1 exacerbates the formation of a disease-promoting microglial phenotype upon amyloid β engulfment. In PD (bottom right), SCD1 is implicated in α-synuclein (α-syn)-induced vesicle trafficking deficits and pathogenic interactions with membranes. Increased SCD1-generated oleic acid (OA) enhances ER-mediated α-syn toxicity, potentially through incorporation into diglycerides (DGs) and lipid droplets (LDs), while also promoting the formation of aggregation-prone α-syn monomers, thus heightening α-syn membrane association and neurotoxicity