ACSL1 (Acyl-CoA Synthetase Long Chain Family Member 1) is an enzyme that catalyzes the conversion of long-chain fatty acids to their CoA esters, the first step in fatty acid metabolism. ACSL1 plays a critical role in lipid metabolism, energy production, and cellular signaling. In the nervous system, ACSL1 is important for neuronal lipid homeostasis, myelination, and has been implicated in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
ACSL1 is a ~78 kDa protein belonging to the Acyl-CoA synthetase family. The protein contains an AMP-binding domain and a motif for fatty acid recognition. ACSL1 localizes to mitochondria, peroxisomes, and the endoplasmic reticulum where it activates fatty acids for beta-oxidation, phospholipid synthesis, or storage as triacylglycerols. Multiple isoforms are generated through alternative splicing.
ACSL1 catalyzes the ATP-dependent thioesterification of long-chain fatty acids (C12-C20) to coenzyme A. This activated fatty acyl-CoA serves as a substrate for: (1) mitochondrial beta-oxidation for energy production; (2) phospholipid synthesis for membrane maintenance; (3) triacylglycerol storage. In neurons, ACSL1 regulates lipid composition of membranes, supports synaptic function, and influences neuroinflammation through production of signaling lipids.
Dysregulation of ACSL1 has been implicated in several neurodegenerative diseases. In Alzheimer's disease, altered ACSL1 expression affects amyloid-beta metabolism and neuroinflammation. In Parkinson's disease, ACSL1 mutations or altered expression may affect mitochondrial function and alpha-synuclein toxicity. ACSL1 also plays roles in demyelinating diseases and metabolic disorders affecting the brain.
ACSL1 modulators are being investigated for metabolic diseases and cancer. In neurodegeneration, targeting ACSL1 may help restore lipid homeostasis, reduce neuroinflammation, or protect mitochondrial function. Small molecule inhibitors and gene therapy approaches are under development.