Mitochondria now implicated
SPG54 HSP, due to a mutation in the DDHD2 gene has been grouped with HSPs exhibiting lipid metabolism abnormalities. This study sheds more light, and poses more questions, on the mechanism underlying this form of HSP by demonstrating the protective role of this gene over mitochondria in mice neurons.
DDHD2/KIAA0725p is a mammalian intracellular phospholipase A1 that exhibits phospholipase and lipase activities. Mutation of the DDHD2gene 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.
SOURCE: Cell Death Dis. 2018 Jul 23;9(8):797. doi: 10.1038/s41419-018-0815-3. PMID: 30038238
Loss of DDHD2, whose mutation causes spastic paraplegia, promotes reactive oxygen species generation and apoptosis.
Maruyama T1, Baba T1,2, Maemoto Y1, Hara-Miyauchi C3, Hasegawa-Ogawa M3, Okano HJ3, Enda Y1, Matsumoto K1, Arimitsu N1,4, Nakao K5, Hamamoto H6,7, Sekimizu K6,7, Ohto-Nakanishi T8, Nakanishi H9, Tokuyama T1, Yanagi S1, Tagaya M10, Tani K1.
1 School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
2 Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, MD, 20892, USA.
3 Division of Regenerative Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
4 Department of Immunology and Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan.
5 Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
6 Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan.
7 Teikyo University Institute of Medical Mycology, 359 Otsuka, Hachioji, Tokyo, 192-0395, Japan.
8 Japan Lipid Technologies LLC, Akita, Akita, 010-0825, Japan.
9 Research Center for Biosignaling, Akita University, Akita, 010-8543, Japan.
10 School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan. [email protected].