Neuronal lipolysis participates in PUFA‐mediated neural function and neurodegeneration

Abstract

Lipid droplets (LDs) are dynamic cytoplasmic organelles present in most eukaryotic cells. The appearance of LDs in neurons is not usually observed under physiological conditions, but is associated with neural diseases. It remains unclear how LD dynamics is regulated in neurons and how the appearance of LDs affects neuronal functions. We discovered that mutations of two key lipolysis genes atgl‐1 and lid‐1 lead to LD appearance in neurons of Caenorhabditis elegans. This neuronal lipid accumulation protects neurons from hyperactivation‐triggered neurodegeneration, with a mild decrease in touch sensation. We also discovered that reduced biosynthesis of polyunsaturated fatty acids (PUFAs) causes similar effects and synergizes with decreased lipolysis. Furthermore, we demonstrated that these changes in lipolysis and PUFA biosynthesis increase PUFA partitioning toward triacylglycerol, and reduced incorporation of PUFAs into phospholipids increases neuronal protection. Together, these results suggest the crucial role of neuronal lipolysis in cell‐autonomous regulation of neural functions and neurodegeneration.

Lipolysis: cellular mechanisms for lipid mobilization from fat stores

“…In humans, loss-of-function mutations in DDHD2 lead to hereditary spastic paraplegia [276][277][278] , a neurodegenerative disorder associated with lipid accumulation in the brain and characterized by spasticity in the lower limbs 276 . Putative DDHD2-dependent mechanisms that may underlie hereditary spastic paraplegia include (1) the accrual of LDs, which would hinder protein and/or lipid trafficking required for synapse assembly 276 , (2) reduced cardiolipin biosynthesis and increased ROS production in mitochondria, which would trigger apoptosis of motor neurons in the spinal cord 279 and (3) altered mobilization of FAs from LDs, which would affect membrane phospholipid composition and neuronal function 280 . Additionally, short-hairpin-RNA-mediated DDHD2 knockdown was shown to impair phospholipid synthesis and sensory axon regeneration after sciatic nerve crush 281 , emphasizing a crucial role for lipolysis in neuron function.…”

A lipid droplet-peroxisome network drives longevity by monounsaturated fatty acids via modulating ether lipid synthesis and ferroptosis

“…Depletion of HSL1/hosl-1 or ATGL/atgl-1, which are involved in lipid droplet hydrolysis (see Fig. 1m) 24,[56][57][58] , led to an increase in lipid droplet number and a slight but significant lifespan extension (Fig. 2a, b, Extended Data Fig.…”

Functions of Stress-Induced Lipid Droplets in the Nervous System

“…Cell-intrinsic metabolic processes also make an important contribution towards preventing LDs from accumulating in neurons. For example, neurons express at least two different TAG lipases—ATGL and DDHD2—and their loss-of-function or chemical inhibition can lead to ectopic LDs in mammalian, Drosophila and C. elegans neurons ( Inloes et al, 2014 ; Inloes et al, 2018 ; Yang et al, 2020a ; Wat et al, 2020 ). In C. elegans , it has also been shown that mutations in an Abhydrolase Domain-Containing Protein 5 (ABHD5)/Comparative Gene Identification-58 (CGI-58) orthologue, a known co-activator of ATGL, or overexpression of DGAT1/2 orthologues leads to ectopic LDs in neurons ( Yang et al, 2020a ).…”

“…For example, neurons express at least two different TAG lipases—ATGL and DDHD2—and their loss-of-function or chemical inhibition can lead to ectopic LDs in mammalian, Drosophila and C. elegans neurons ( Inloes et al, 2014 ; Inloes et al, 2018 ; Yang et al, 2020a ; Wat et al, 2020 ). In C. elegans , it has also been shown that mutations in an Abhydrolase Domain-Containing Protein 5 (ABHD5)/Comparative Gene Identification-58 (CGI-58) orthologue, a known co-activator of ATGL, or overexpression of DGAT1/2 orthologues leads to ectopic LDs in neurons ( Yang et al, 2020a ). Similarly, some perilipins protect LDs from lipolysis, and overexpression of either the Lsd-1 or Lsd-2 perilipins in Drosophila photoreceptors results in a large increase in the usually sparse LDs in these neurons ( Girard et al, 2021 ).…”

“…TAG lipolysis in neurons is not, however, universally beneficial. In a C. elegans genetic model of excitotoxicity, LDs accumulate in neurons during their degeneration but this is rescued by inactivation of ATGL or ABHD5/CGI-58 and worsened by C20 PUFA incorporation into phospholipids ( Yang et al, 2020a ). Hence, in this excitotoxic model, TAG lipolysis in neurons exacerbates their degeneration, perhaps because it redirects PUFA into membranes where they are vulnerable to peroxidation.…”