title: Insufficient ER-stress response causes selective mouse cerebellar granule cell degeneration resembling that seen in congenital disorders of glycosylation.
abstract: BACKGROUND
  Congenital disorders of glycosylation (CDGs) are inherited diseases caused by glycosylation defects. Incorrectly glycosylated proteins induce protein misfolding and endoplasmic reticulum (ER) stress. The most common form of CDG, PMM2-CDG, is caused by deficiency in the cytosolic enzyme phosphomannomutase 2 (PMM2). Patients with PMM2-CDG exhibit a significantly reduced number of cerebellar Purkinje cells and granule cells. The molecular mechanism underlying the specific cerebellar neurodegeneration in PMM2-CDG, however, remains elusive.
  
  
  RESULTS
  Herein, we report that cerebellar granule cells (CGCs) are more sensitive to tunicamycin (TM)-induced inhibition of total N-glycan synthesis than cortical neurons (CNs). When glycan synthesis was inhibited to a comparable degree, CGCs exhibited more cell death than CNs. Furthermore, downregulation of PMM2 caused more CGCs to die than CNs. Importantly, we found that upon PMM2 downregulation or TM treatment, ER-stress response proteins were elevated less significantly in CGCs than in CNs, with the GRP78/BiP level showing the most significant difference. We further demonstrate that overexpression of GRP78/BiP rescues the death of CGCs resulting from either TM-treatment or PMM2 downregulation.
  
  
  CONCLUSIONS
  Our results indicate that the selective susceptibility of cerebellar neurons to N-glycosylation defects is due to these neurons' inefficient response to ER stress, providing important insight into the mechanisms of selective neurodegeneration observed in CDG patients.
authors.forename: Liangwu
authors.initials: L
authors.lastname: Sun
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Kun
authors.initials: K
authors.lastname: Zhou
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.forename: Yun-Wu
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Neurodegenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA. xuh@sanfordburnham.org.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology; D018981:Congenital Disorders of Glycosylation / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017875:Phosphotransferases (Phosphomutases) / Q000378:metabolism; D014415:Tunicamycin / Q000633:toxicity
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D014415:Tunicamycin; D017875:Phosphotransferases (Phosphomutases); C513491:Pmm2 protein, mouse