Abstract
DDHD2/KIAA0725p is a mammalian intracellular phospholipase A1 that exhibits phospholipase and lipase activities. Mutation of the DDHD2 gene causes hereditary spastic paraplegia (SPG54), an inherited neurological disorder characterized by lower limb spasticity and weakness. Although previous studies demonstrated lipid droplet accumulation in the brains of SPG54 patients and DDHD2 knockout mice, the cause of SPG54 remains elusive. Here, we show that ablation of DDHD2 in mice induces age-dependent apoptosis of motor neurons in the spinal cord. In vitro, motor neurons and embryonic fibroblasts from DDHD2 knockout mice fail to survive and are susceptible to apoptotic stimuli. Chemical and probe-based analysis revealed a substantial decrease in cardiolipin content and an increase in reactive oxygen species generation in DDHD2 knockout cells. Reactive oxygen species production in DDHD2 knockout cells was reversed by the expression of wild-type DDHD2, but not by an active-site DDHD2 mutant, DDHD2 mutants related to hereditary spastic paraplegia, or DDHD1, another member of the intracellular phospholipase A1 family whose mutation also causes spastic paraplegia (SPG28). Our results demonstrate the protective role of DDHD2 for mitochondrial integrity and provide a clue to the pathogenic mechanism of SPG54.
Highlights
Hereditary spastic paraplegia (HSP) is a diverse group of neurological disorders characterized by lower limb spasticity and weakness[1,2]
Neurons in the motor cortex of DDHD2 KO mice survived, similar to those from the WT mice (Supplementary Figure 1f). These results suggest that the DDHD2 deficiency causes degeneration of motor neurons in the spinal cord, not the motor cortex, in an age-dependent manner
Because the major source of reactive oxygen species (ROS) in cells is mitochondria, we examined whether ROS formation in the absence of DDHD2 occurs at mitochondria
Summary
Hereditary spastic paraplegia (HSP) is a diverse group of neurological disorders characterized by lower limb spasticity and weakness[1,2]. These symptoms are due to lengthdependent axonopathy of corticospinal motor neurons, sometimes associated with a loss of cortical neurons and anterior horn cells[3]. The intracellular phospholipase A1 (PLA1) protein family is a relatively recently discovered lipid-metabolizing enzyme family, and characterized by the presence of the short lipase active-site sequence Gly-X-Ser-X-Gly (X represents any amino acid) and a C-terminal DDHD (named after the presence of conserved three Asp residues and one His residue) domain. DDHD1 is highly expressed in brain and Official journal of the Cell Death Differentiation Association
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
