Glycan degradation promotes macroautophagy

Baudot, Alice D.; Wang, Victoria M.-Y.; Leach, Josh D; O’Prey, Jim; Long, Jaclyn; Paulus-Hock, Viola; Lilla, Sérgio; Thomson, David M.; Greenhorn, John; Ghaffar, Farah Naz; Nixon, Colin; Helfrich, Miep; Strathdee, Douglas; Pratt, Judith A.; Marchesi, Francesco; Zanivan, Sara; Ryan, Kevin M.

doi:10.1073/pnas.2111506119

Cited by 7 publications

(4 citation statements)

References 58 publications

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“…Inclusions with ultrastructures similar to some of the proband’s nonvacuolar inclusions have been shown in brain cells from murine LSD models and classified as autophagosomes [ 48 , 108 , 109 , 110 ]. Although we have not found previous reports of impaired autophagic flux in α-mannosidosis, impaired autophagic flux has been demonstrated in a mouse model of the LSD, fucosidosis [ 111 ]. Similar to α-mannosidosis, fucosidosis is associated with the lysosomal accumulation of oligosaccharides due to a deficiency of a gene that encodes a lysosomal glycosidase required for the complete catabolism of the asparagine-linked glycan side chains of glycoproteins [ 112 ].…”

Section: Discussioncontrasting

confidence: 76%

A Homozygous MAN2B1 Missense Mutation in a Doberman Pinscher Dog with Neurodegeneration, Cytoplasmic Vacuoles, Autofluorescent Storage Granules, and an α-Mannosidase Deficiency

Bullock,

Johnson,

Pattridge

et al. 2023

Genes

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A 7-month-old Doberman Pinscher dog presented with progressive neurological signs and brain atrophy suggestive of a hereditary neurodegenerative disorder. The dog was euthanized due to the progression of disease signs. Microscopic examination of tissues collected at the time of euthanasia revealed massive accumulations of vacuolar inclusions in cells throughout the central nervous system, suggestive of a lysosomal storage disorder. A whole genome sequence generated with DNA from the affected dog contained a likely causal, homozygous missense variant in MAN2B1 that predicted an Asp104Gly amino acid substitution that was unique among whole genome sequences from over 4000 dogs. A lack of detectable α-mannosidase enzyme activity confirmed a diagnosis of a-mannosidosis. In addition to the vacuolar inclusions characteristic of α-mannosidosis, the dog exhibited accumulations of autofluorescent intracellular inclusions in some of the same tissues. The autofluorescence was similar to that which occurs in a group of lysosomal storage disorders called neuronal ceroid lipofuscinoses (NCLs). As in many of the NCLs, some of the storage bodies immunostained strongly for mitochondrial ATP synthase subunit c protein. This protein is not a substrate for α-mannosidase, so its accumulation and the development of storage body autofluorescence were likely due to a generalized impairment of lysosomal function secondary to the accumulation of α-mannosidase substrates. Thus, it appears that storage body autofluorescence and subunit c accumulation are not unique to the NCLs. Consistent with generalized lysosomal impairment, the affected dog exhibited accumulations of intracellular inclusions with varied and complex ultrastructural features characteristic of autophagolysosomes. Impaired autophagic flux may be a general feature of this class of disorders that contributes to disease pathology and could be a target for therapeutic intervention. In addition to storage body accumulation, glial activation indicative of neuroinflammation was observed in the brain and spinal cord of the proband.

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Section: Discussioncontrasting

confidence: 76%

A Homozygous MAN2B1 Missense Mutation in a Doberman Pinscher Dog with Neurodegeneration, Cytoplasmic Vacuoles, Autofluorescent Storage Granules, and an α-Mannosidase Deficiency

Bullock,

Johnson,

Pattridge

et al. 2023

Genes

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“…DNA damage has been shown to induce autophagy in mammalian cells and yeast [21,22], and in our previous work, we also found that DNA damage can induce autophagy in C. albicans [40]. The traditional and best-studied autophagy is macroautophagy, also known as non-selective autophagy [41], which is usually activated under nitrogen starvation conditions [42]. Atg proteins play an essential role in autophagy, regulating autophagy at various stages [16][17][18][19][20].…”

Section: Comparison Of the Role Of Atg Proteins In Dna Damage-induced...mentioning

confidence: 78%

Mec1-Rad53 Signaling Regulates DNA Damage-Induced Autophagy and Pathogenicity in Candida albicans

Du,

Dong,

Zuo

et al. 2023

JoF

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DNA damage activates the DNA damage response and autophagy in C. albicans; however, the relationship between the DNA damage response and DNA damage-induced autophagy in C. albicans remains unclear. Mec1-Rad53 signaling is a critical pathway in the DNA damage response, but its role in DNA damage-induced autophagy and pathogenicity in C. albicans remains to be further explored. In this study, we compared the function of autophagy-related (Atg) proteins in DNA damage-induced autophagy and traditional macroautophagy and explored the role of Mec1-Rad53 signaling in regulating DNA damage-induced autophagy and pathogenicity. We found that core Atg proteins are required for these two types of autophagy, while the function of Atg17 is slightly different. Our results showed that Mec1-Rad53 signaling specifically regulates DNA damage-induced autophagy but has no effect on macroautophagy. The recruitment of Atg1 and Atg13 to phagophore assembly sites (PAS) was significantly inhibited in the mec1Δ/Δ and rad53Δ/Δ strains. The formation of autophagic bodies was obviously affected in the mec1Δ/Δ and rad53Δ/Δ strains. We found that DNA damage does not induce mitophagy and ER autophagy. We also identified two regulators of DNA damage-induced autophagy, Psp2 and Dcp2, which regulate DNA damage-induced autophagy by affecting the protein levels of Atg1, Atg13, Mec1, and Rad53. The deletion of Mec1 or Rad53 significantly reduces the ability of C. albicans to systematically infect mice and colonize the kidneys, and it makes C. albicans more susceptible to being killed by macrophages.

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“…Yu et al proposed using N-glycans as biomarkers for the early diagnosis of Alzheimer’s disease [ 36 ]. Glycan degradation is known to promote macroautophagy [ 37 ]. Most genes associated with this process ( Figure 6 ), such as FUCA1 , NEU1 , MAN2C1 , GLB1 , HEXA , AGA , and MAN2B 2, had lower expression levels in the TWAS.…”

Section: Discussionmentioning

confidence: 99%

Cognitive Impairment in Nonagenarians: Potential Metabolic Mechanisms Revealed by the Synergy of In Silico Gene Expression Modeling and Pathway Enrichment Analysis

Mamchur,

Zelenova,

Dzhumaniiazova

et al. 2024

IJMS

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Previous studies examining the molecular and genetic basis of cognitive impairment, particularly in cohorts of long-living adults, have mainly focused on associations at the genome or transcriptome level. Dozens of significant dementia-associated genes have been identified, including APOE, APOC1, and TOMM40. However, most of these studies did not consider the intergenic interactions and functional gene modules involved in cognitive function, nor did they assess the metabolic changes in individual brain regions. By combining functional analysis with a transcriptome-wide association study, we aimed to address this gap and examine metabolic pathways in different areas of the brain of older adults. The findings from our previous genome-wide association study in 1155 older adults, 179 of whom had cognitive impairment, were used as input for the PrediXcan gene prediction algorithm. Based on the predicted changes in gene expression levels, we conducted a transcriptome-wide association study and functional analysis using the KEGG and HALLMARK databases. For a subsample of long-living adults, we used logistic regression to examine the associations between blood biochemical markers and cognitive impairment. The functional analysis revealed a significant association between cognitive impairment and the expression of NADH oxidoreductase in the cerebral cortex. Significant associations were also detected between cognitive impairment and signaling pathways involved in peroxisome function, apoptosis, and the degradation of lysine and glycan in other brain regions. Our approach combined the strengths of a transcriptome-wide association study with the advantages of functional analysis. It demonstrated that apoptosis and oxidative stress play important roles in cognitive impairment.

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Glycan degradation promotes macroautophagy

Cited by 7 publications

References 58 publications

A Homozygous MAN2B1 Missense Mutation in a Doberman Pinscher Dog with Neurodegeneration, Cytoplasmic Vacuoles, Autofluorescent Storage Granules, and an α-Mannosidase Deficiency

A Homozygous MAN2B1 Missense Mutation in a Doberman Pinscher Dog with Neurodegeneration, Cytoplasmic Vacuoles, Autofluorescent Storage Granules, and an α-Mannosidase Deficiency

Mec1-Rad53 Signaling Regulates DNA Damage-Induced Autophagy and Pathogenicity in Candida albicans

Cognitive Impairment in Nonagenarians: Potential Metabolic Mechanisms Revealed by the Synergy of In Silico Gene Expression Modeling and Pathway Enrichment Analysis

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