The PtdIns(3,4)P2 phosphatase INPP4A is a suppressor of excitotoxic neuronal death

• Published in: Nature (London) 2010-05, Vol.465 (7297), p.497-501
• Main Authors: Sasaki, Junko, Kofuji, Satoshi, Itoh, Reietsu, Momiyama, Toshihiko, Takayama, Kiyohiko, Murakami, Haruka, Chida, Shinsuke, Tsuya, Yuko, Takasuga, Shunsuke, Eguchi, Satoshi, Asanuma, Ken, Horie, Yasuo, Miura, Kouichi, Davies, Elizabeth Michele, Mitchell, Christina, Yamazaki, Masakazu, Hirai, Hirokazu, Takenawa, Tadaomi, Suzuki, Akira, Sasaki, Takehiko
• Format: Article
• Language: English
• Subjects: 631/378/1934; 631/45/607/1164; 631/80; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Humanities and Social Sciences; letter; Medical sciences; Miscellaneous; multidisciplinary; Neurology; Pharmacology. Drug treatments; Science
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09023

INPP4A suppression of excitotoxic neuronal death Junko Sasaki and colleagues demonstrate a critical role for inositol polyphosphate phosphatase 4A (INPP4A), a PtdIns(3,4)P 2 phosphatase, in maintaining the integrity of the brain. Mice that lack INPP4A have neurodegeneration in the striatum and suffer from severe involuntary movements. They further show that INPP4A, when present, protects neurons from NMDA type glutamate receptor-mediated excitotoxic cell death. The authors present evidence to suggest that INPP4A can keep neurons alive by downregulating NMDARs and thus decreasing cellular sensitivity to glutamate stimulation. The enzyme inositol polyphosphate phosphatase 4A (INPP4A) removes phosphate groups from phosphatidylinositol-3,4-bisphosphate, a key cellular lipid. Here, a crucial role for INPP4A in maintaining the integrity of the brain is described. Mice that lack this enzyme suffer from neurodegeneration in the striatum of the brain, as well as severe involuntary movements. When present, INPP4A protects neurons from a particular type of cell death. Phosphorylated derivatives of phosphatidylinositol, collectively referred to as phosphoinositides, occur in the cytoplasmic leaflet of cellular membranes and regulate activities such as vesicle transport, cytoskeletal reorganization and signal transduction 1 , 2 . Recent studies have indicated an important role for phosphoinositide metabolism in the aetiology of diseases such as cancer, diabetes, myopathy and inflammation 3 , 4 , 5 . Although the biological functions of the phosphatases that regulate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) have been well characterized, little is known about the functions of the phosphatases regulating the closely related molecule phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P 2 ). Here we show that inositol polyphosphate phosphatase 4A (INPP4A), a PtdIns(3,4)P 2 phosphatase, is a suppressor of glutamate excitotoxicity in the central nervous system. Targeted disruption of the Inpp4a gene in mice leads to neurodegeneration in the striatum, the input nucleus of the basal ganglia that has a central role in motor and cognitive behaviours. Notably, Inpp4a -/- mice show severe involuntary movement disorders. In vitro , Inpp4a gene silencing via short hairpin RNA renders cultured primary striatal neurons vulnerable to cell death mediated by N -methyl- d -aspartate-type glutamate receptors (NMDARs). Mechanistically, INPP4A is found at the postsynaptic d