DHA incorporation into neuronal membranes is critical for protection against age-related neuroinflammation and neurological disease

Abstract: Brain membrane acyl-chain profiles are highly diverse across cell types and brain regions, yet the regulatory mechanisms governing the composition of these acyl-chains and subsequent influence on neurological health remains incompletely understood. We recently discovered that neuronal enrichment of the neuroprotective fatty acid, docosahexaenoic acid (DHA), requires the enzyme long-chain acyl-CoA synthetase 6 (ACSL6). ACSL6 is an enzyme that initiates cellular fatty acid metabolism, prefers DHA, and is enriched in the brain. Genetic deletion of ACSL6 in mice resulted in large and specific reductions (35-72%) in neuronal DHA-containing phospholipids. This neuron-specific depletion of membrane DHA in mice disrupts motor and memory function and leads to early-onset age-related neuroinflammation. These data demonstrate the importance of ACSL6 mediated lipid metabolism in neurological health and aging. Using this model of neuronal membrane DHA deficit, we have now linked ACSL6 metabolism with the biology of alpha-synuclein – a mediator of age-related neurodegenerative diseases such as Parkinson’s disease, dementias, and other synucleinopathies. Alpha-synuclein is well known to interact with DHA, yet how these interactions are regulated and the influence of these interactions on alpha-synuclein-related diseases remain unknown. Combining ACSL6 deficient mice with a model of synucleinopathy resulted in increased brain alpha-synuclein oligomerization and early lethality. Together, these data suggest a critical role for ACSL6-mediated lipid metabolism in synucleinopathies, neurological health, and aging.