Fighting the Cause of Alzheimer’s and GNE Myopathy

Abstract

Age is the common risk factor for both neurodegenerative and neuromuscular diseases. Alzheimer disease (AD), a neurodegenerative disorder, causes dementia with age progression while GNE myopathy (GNEM), a neuromuscular disorder, causes muscle degeneration and loss of muscle motor movement with age. Individuals with mutations in presenilin or amyloid precursor protein (APP) gene develop AD while mutations in GNE (UDP N-acetylglucosamine 2 epimerase/N-acetyl Mannosamine kinase), key sialic acid biosynthesis enzyme, cause GNEM. Although GNEM is characterized with degeneration of muscle cells, it is shown to have similar disease hallmarks like aggregation of Aβ and accumulation of phosphorylated tau and other misfolded proteins in muscle cell similar to AD. Similar impairment in cellular functions have been reported in both disorders such as disruption of cytoskeletal network, changes in glycosylation pattern, mitochondrial dysfunction, oxidative stress, upregulation of chaperones, unfolded protein response in ER, autophagic vacuoles, cell death, and apoptosis. Interestingly, AD and GNEM are the two diseases with similar phenotypic condition affecting neuron and muscle, respectively, resulting in entirely different pathology. This review represents a comparative outlook of AD and GNEM that could lead to target common mechanism to find a plausible therapeutic for both the diseases.

Altered Actin Dynamics in Cell Migration of GNE Mutant Cells

“…The process of sialylation of glycoproteins starts from the biosynthesis of sialic acid from UDP-N-acetylglucosamine. The critical enzyme involved in the biosynthesis of sialic acid is GNE (UDP-N-acetylglucosamine 2-Epimerase/N-acetylmannosamine kinase) (Devi et al, 2018 ). Mutations in GNE cause two different types of genetic disorder—sialuria and GNE myopathy.…”

Elucidation of ER stress and UPR pathway in sialic acid‐deficient cells: Pathological relevance to GNEM

“…Besides hyposialylation, other cellular defects have been reported in GNE mutant cells such as cell adhesion, ER stress, upregulation of chaperones, cytoskeletal disorganization, mitochondrial dysfunction, autophagy, and cell apoptosis 14 . Presence of autophagic rimmed vacuoles containing deposits of β‐amyloid, α‐synuclein, tau, and transactive response DNA binding protein (TDP‐43) protein has been observed in GNEM muscle biopsies 15 .…”

“…Besides hyposialylation, other cellular defects have been reported in GNE mutant cells such as cell adhesion, ER stress, upregulation of chaperones, cytoskeletal disorganization, mitochondrial dysfunction, autophagy, and cell apoptosis. 14 Presence of autophagic rimmed vacuoles containing deposits of β-amyloid, α-synuclein, tau, and transactive response DNA binding protein (TDP-43) protein has been observed in GNEM muscle biopsies. 15 Differential expression of proteins associated with stress response to unfolded protein namely, crystalline alpha B, heat shock 27 kDa protein 1 and heat shock 70 (HSP 70) kDa protein 8 isoform 1 was indicated in GNEM specimens.…”