Functional Contribution of the Spastic Paraplegia-Related Triglyceride Hydrolase DDHD2 to the Formation and Content of Lipid Droplets

Abstract

Deleterious mutations in the serine lipase DDHD2 are a causative basis of complex hereditary spastic paraplegia (HSP, subtype SPG54) in humans. We recently found that DDHD2 is a principal triglyceride hydrolase in the central nervous system (CNS) and that genetic deletion of this enzyme in mice leads to ectopic lipid droplet (LD) accumulation in neurons throughout the brain. Nonetheless, how HSP-related mutations in DDHD2 relate to triglyceride metabolism and LD formation remains poorly understood. Here, we have characterized a set of HSP-related mutations in DDHD2 and found that they disrupt triglyceride hydrolase activity in vitro and impair the capacity of DDHD2 to protect cells from LD accumulation following exposure to free fatty acid, an outcome that was also observed with a DDHD2-selective inhibitor. We furthermore isolated and characterized LDs from brain tissue of DDHD2 mice, revealing that they contain both established LD-associated proteins identified previously in other organs and CNS-enriched proteins, including several proteins with genetic links to human neurological disease. These data, taken together, indicate that the genetic inactivation of DDHD2, as caused by HSP-associated mutations, substantially perturbs lipid homeostasis and the formation and content of LDs, underscoring the importance of triglyceride metabolism for normal CNS function and the key role that DDHD2 plays in this process.

Lipid Droplets in Neurodegenerative Disorders

“…For example, DDH2 domain containing protein 2 (DDHD2) is a triglyceride hydrolase in the brain that is implicated in recessive complex HSP. The systemic genetic knockout and pharmacological inhibition of DDH2 resulted in large-scale accumulation of LDs within the CNS, but not elsewhere (Inloes et al, 2018). These data indicate a link to TAG metabolism, as the inhibition of DDHD2 affects lipid homeostasis and LD number.…”

Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia

“…In a mouse model for spastic paraplegia type 54 (OMIM 615033), biallelic DDHD2 variants led to a significant accumulation of triacylglycerols in the CNS. This triacylglycerol accumulation correlated with an increase in amounts and size of lipid droplets within neurons when compared to wild-type mice, where lipid droplets are rarely seen (Inloes et al , 2018). Accumulation of lipid droplets within the CNS is potentially neurotoxic and has been seen previously in neurodegenerative conditions such as Alzheimer’s disease (Gómez-Ramos and Asunción Morán, 2007; Liu et al , 2017), suggesting that the neutral lipid accumulation in ET deficiency could play a causative role in the degenerative phenotype.…”

High‐dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy

“…In Ddhd2 −/− mice, a greater amount of TAGs in the form of LDs accumulates in the brain and spinal cord (25). The disruption of TAG hydrolase activity impairs the capacity to protect cells from LD accumulation following free fatty acid exposure (26). These results converge into a strong body of evidence directly connecting the dysfunction of LDs to decreased protection from lipidcaused oxidative stress, leading to motoneuron disease.…”