Membralin-deficient astrocytes triggered motor neuron death LuLin Jiang1, Bing Zhu1, Yingjun Zhao1, Timothy Huang1, Dongxian Zhang1, Huaxi Xu1* 1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA *Corresponding Author Membralin is a newly identified endoplasmic-reticulum-associated degradation (ERAD) component. Previously, we found that deficiency in membralin impaired the turnover of nicastrin, one of the key subunit for -secretase. Downregulation of membralin in an Alzheimer's Disease (AD) mouse model elevated -secretase activity and exaggerated b-amyloid associated neurotoxic effects and memory decline. Currently, we focus on the cell-type specific effects of membralin in the central nervous system. Cre-Loxp conditional knockout systems were used to selectively delete membralin in different type of neural cells. We also used primary astrocytes to co-culture with mouse embryonic stem cell derived motor neurons. Western blot, immunostaining, and glutamate measurement by GC-MS were used in the study. We find membralin in astrocytes played an important role in mediating motor neuron survival through the regulation of Glt1, the astrocyte-specific glutamate transporter. Glt1 markedly reduced in the membralin-deficient astrocytes and extracellular glutamate level significantly increased in the conditioned medium collected from membralin-deficient astrocytes. Our result indicates that the non-cell-autonomous effect induced by membralin-deficient astrocytes triggers the motor neuron death.
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