Palmitoylation and function of glial glutamate transporter-1 is reduced in the YAC128 mouse model of Huntington disease.
Excitotoxicity plays a key role in the selective vulnerability of striatal neurons in Huntington disease (HD). Decreased glutamate uptake by glial cells could account for the excess glutamate at the synapse in patients as well as animal models of HD. The major molecule responsible for clearing glutamate at the synapses is glial glutamate transporter GLT-1. In this study, we show that GLT-1 is palmitoylated at cysteine38 (C38) and further, that this palmitoylation is drastically reduced in HD models both in vitro and in vivo. Palmitoylation is required for normal GLT-1 function. Blocking palmitoylation either with the general palmitoylation inhibitor, 2-bromopalmitate, or with a GLT-1 C38S mutation, severely impairs glutamate uptake activity. In addition, GLT-1-mediated glutamate uptake is indeed impaired in the YAC128 HD mouse brain, with the defect in the striatum evident as early as 3 months prior to obvious neuropathological findings, and in both striatum and cortex at 12 months. These phenotypes are not a result of changes in GLT1 protein expression, suggesting a crucial role of palmitoylation in GLT-1 function. Thus, it appears that impaired GLT-1 palmitoylation is present early in the pathogenesis of HD, and may influence decreased glutamate uptake, excitotoxicity, and ultimately, neuronal cell death in HD.
Huang
Kun
K
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
Kang
Martin H
MH
Askew
Caitlin
C
Kang
Rujun
R
Sanders
Shaun S
SS
Wan
Junmei
J
Davis
Nicholas G
NG
Hayden
Michael R
MR
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006816:Huntington Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D054878:Lipoylation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009457:Neuroglia / Q000378:metabolism*; D051381:Rats
D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; D003545:Cysteine