Abstract
BackgroundCongenital 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.ResultsHerein, 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.ConclusionsOur 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.
Highlights
Congenital disorders of glycosylation (CDGs) are inherited diseases caused by glycosylation defects
Our results revealed that murine cerebellar granule cells (CGCs) are much more sensitive to glycosylation defects and associated cell death than cortical neurons (CNs), and that a less efficient response to glycosylation disruption-induced endoplasmic reticulum (ER) stress in CGCs may be responsible for their selective vulnerability and neurodegeneration in the patients
The results showed that TM treatments inhibited glycan synthesis in both CGCs and CNs in a dose-dependent manner (Figure 1A)
Summary
Congenital disorders of glycosylation (CDGs) are inherited diseases caused by glycosylation defects. Congenital disorders of glycosylation (CDGs) are inherited autosomal recessive disorders caused by defects in the glycosylation pathway, and display a broad spectrum of clinical features such as psychomotor retardation, hypotonia, intractable seizures, stroke-like episodes, internal strabismus, cyclic vomiting, hydrops fetalis, and immunocytochemical examination of cerebellar tissues from PMM2-CDG patients show partial atrophy of cerebellar folia with a severe loss of Purkinje cells and granule cells, and various morphological changes in the remaining Purkinje cells. It is unclear why cerebellar neurons are selectively susceptible to glycosylation defects in these patients. Genome-wide analysis of the UPR in fibroblasts from CDG patients show that CDG cells have chronic ER stress, and that the genes encoding components of the UPR are moderately induced [12]
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