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Principal Investigator: GARY B RUVKUN
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $431,960
Funding agency: National Institute on Aging
Project Summary/Abstract:
Our discovery that the NGLY1/PNG-1 deglycosylation enzyme mediates the protein editing of N-
glycosylated asparagines to aspartic acid of the SKN-1A transcription factor to increase proteasomal
capacity is highly relevant to protein aggregation diseases, such as Alzheimer’s disease and ADRD.
NGLY1 N to D editing of SKN-1A also mediates the up-regulation of proteasome biogenesis in face of
protein aggregation challenges including to human Ab, a key trigger of AD and ADRD. Precisely the
same PNG-1/NGLY1, DDI-1, SKN-1A pathway acts in human tumor cells to mediate responses to the
protein assembly and degradation challenges of aneuploidy. Our informatic analysis shows a strong
signature of NGLY1-mediated protein editing in the SARS-CoV-2 Spike protein, motivating our genetic
analysis of anti-viral response defects in C. elegans png-1, ddi-1, and skn-1a mutants. We also explore
how decreased mitochondrial function increases longevity and antiviral defense in C. elegans. C.
elegans uses a system homologous to the mammalian mitochondrial MAVS to RNA helicase system that
is coupled to NF-kB antiviral cascades in mammals and to RNA interference in C. elegans to activate
antiviral defense. Mutations in C. elegans drh-1,the orthologue of mammalian MDA5 RNA helicase, a
key player in mammalian mitochondrial to interferon antiviral defense, suppress the enhanced RNAi and
suppress the lifespan extension of mitochondrial mutants, supporting the model that enhanced antiviral
defense as a key anti-aging output from mitochondrial mutations. The dramatic increases in C. elegans
longevity that are observed in C. elegans insulin-signaling mutants also induce enhanced RNAi, an
antiviral response. This intersects with the dramatically increased vulnerability to viruses in the elderly,
especially for Sars-Cov2, where the vast majority of deaths were over 75 years old. We hypothesize that
the striking increase in AD and ADRD during aging may be caused by the sum of late onset viral
infections that challenge proteasomal capacity. Our genetic analysis discovered that the activation of the
CMTR-1 RNA methylase suppresses the hyperoxia lethality of complex I mutants. The phylogenetic
profile of CMTR-1 shows that it is very similar to the C. elegans cat-2 tyrosine dioxygenase that mediates
dopamine synthesis. We will test if CMTR-1 RNA methylates the cat-2 and other mRNAs that encode
dopamine production and whether this RNA methylation is responsive to oxygen. The mitochondrion is
implicated in Parkinson’s disease by the human mitochondrial Parkin ubiquitin ligase and PINK1 kinase,
and we will test whether C. elegans mutations in the orthologues of these mitochondrial Parkinson’s
genetic risk genes pdr-1 (Parkin) or pink-1 interact with the CMTR-1 RNA methylase to cat-2 mRNA
regulatory interaction.
Terms: <2-hydroxyphenylalanine><2-tyrosine><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><AD dementia><AD related dementia><ADRD><ATP-protein phosphotransferase><Adrenal Glands><Adrenals><Aging><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimers Dementia><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Anatomic Sites><Anatomic structures><Anatomy><Aneuploid><Aneuploidy><Animals><Anti-viral Response><Asparagine><Aspartic Acid><Aspartic Endopeptidases><Aspartic Proteinases><Aspartyl Proteases><Aspartyl Proteinases><Autoregulation><Aβ><Basal Transcription Factor><Basal transcription factor genes><Binding Site Domain><Biogenesis><Biological><Body Tissues><Bortezomib><C elegans><C. elegans><C.elegans><COVID-19 S protein><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 virus><Caenorhabditis elegans><Capsid Proteins><Carboxyl (Acid) Proteinases><Carboxylic Proteinases><Cats><Cats Mammals><Cell Body><Cell Nucleus><Cells><Cessation of life><Chimera Protein><Chimeric Proteins><Client><CoV-2><CoV2><Coat Proteins><Complex><Coupled><DA Neuron><DNA Recombination><Death><Defect><Development><Dexamethasone><Dioxygenases><Disease><Disorder><Domestic Cats><Dopamine><Dopamine neuron><Drug Metabolic Detoxication><Drug Metabolic Detoxification><EC 2.1.1><EC 2.1.1.31-36><Elderly><Electrons><Enzyme Gene><Enzymes><Esteroproteases><Face><Feline Species><Felis catus><Felis domestica><Felis domesticus><Felis sylvestris catus><Fusion Protein><Future><Gases><Gene Copy Number><Gene Dosage><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Recombination><Genetic Risk><Genetic analyses><Genetic defect><Genome><Genomics><Glycans><Glycopeptidase><Glycopeptide N-glycosidase><Homeostasis><Human><Hydroxytyramine><Hyperoxia><IFN><Immunity><Immunoglobulin Enhancer-Binding Protein><Increase lifespan><Informatics><Interferons><Intestinal><Intestines><Kinase Family Gene><Kinases><L-Asparagine><L-Aspartic Acid><Lacrimal Glands><Lacrimal gland structure><Length of Life><Ligand Binding Domain><Location><Longevity><Macropain><Macroxyproteinase><Mammalia><Mammals><Mediating><Messenger RNA><Metabolic Drug Detoxications><Metabolic Glycosylation><Metabolism of Toxic Agents><Methylation><Methyltransferase><Mitochondria><Modeling><Modern Man><Molecular><Monitor><Multicatalytic Proteinase><Muscle><Muscle Tissue><Mutation><N-Glycanase><N-Oligosaccharide Glycopeptidase><NF-kB><NF-kappa B><NF-kappaB><NFKB><Negative Beta Particle><Negatrons><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Polyadenylated RNA><Nuclear><Nuclear Factor kappa B><Nuclear Hormone Receptor Superfamily><Nuclear Hormone Receptors><Nuclear Transcription Factor NF-kB><Nucleus><O element><O2 element><Oocytes><Origin of Life><Output><Ovocytes><Oxygen><PARK6><PARK6 gene><PARK6 protein><PINK1><PINK1 gene><PINK1 gene product><PINK1 protein><PTEN induced kinase 1><PTEN induced putative kinase 1><PTEN-induced putative kinase><Paralysis Agitans><Parkin><Parkin gene><Parkinson><Parkinson Disease><Parkinson disease 6 gene><Partial Pressure><Pathway interactions><Pedigree><Peptidases><Peptide Hydrolases><Peptide N-Glycosidase><Peptide-N-Glycanase><Phosphatase and tensin homolog induced kinase 1><Phosphotransferase Gene><Phosphotransferases><Phylogenetic Analysis><Phylogenetic Pattern><Phylogenetics><Physiological Homeostasis><Polysaccharides><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Primary Parkinsonism><Primary Senile Degenerative Dementia><Production><Prosome><Protease Gene><Proteases><Proteasome><Proteasome Endopeptidase Complex><Proteasome Inhibitor><Protein Kinase><Proteinases><Proteins><Proteolytic Enzymes><Proteosome><RNA><RNA Gene Products><RNA Helicase><RNA Interference><RNA Methylases><RNA Seq><RNA Silencing><RNA Virus Infections><RNA methylation><RNA sequencing><RNA viral infection><RNA, Transfer, Methyltransferases><RNAi><RNAseq><Receptor Gene><Recombination><Ribonucleic Acid><Risk Factors><Risk-associated variant><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Secretory Cell><Sequence-Specific Posttranscriptional Gene Silencing><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Short interfering RNA><Small Interfering RNA><Small RNA><Stress><Sum><System><T RNA Methyltransferases><Testing><Tissues><Transcription Factor NF-kB><Transcription Factor Proto-Oncogene><Transcription factor genes><Transphosphorylases><Tumor Cell><Tyrosine><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Up-Regulation><Upregulation><Viral><Viral Coat Proteins><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Genome><Viral Outer Coat Protein><Viral Proteins><Virion><Virus><Virus Diseases><Virus Integration><Virus Particle><Virus Replication><Vitellogenins><Wuhan coronavirus><a beta peptide><abeta><advanced age><age associated disease><age associated disorder><age associated impairment><age dependent disease><age dependent disorder><age dependent impairment><age related human disease><age-related disease><age-related disorder><age-related impairment><aging associated mechanism><aging mechanism><aging pathway><aging related mechanism><amyloid beta><amyloid-b protein><anti aging><anti geronic><antiaging><aspartate protease><aspartic protease><beta amyloid fibril><biologic><biological mechanism of age><biological pathways of age><bowel><cell type><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19 virus><deep sequencing><detoxification><developmental><dopaminergic neuron><elongating the lifespan><extend life span><extend lifespan><faces><facial><fusion gene><gain of function><genetic analysis><genetic element><genetic pedigree><genome mutation><geriatric><glycogen synthase a kinase><glycosylation><hCoV19><human disease><hydroxyalkyl protein kinase><hyperoxygenation><insoluble aggregate><insulin signaling><kappa B Enhancer Binding Protein><life span><lifespan><lifespan extension><mRNA><methylase><mitochondrial><mitochondrial dysfunction><mitochondrial genome><mitochondrial membrane><multicatalytic endopeptidase complex><muscular><mutant><nCoV2><nematode genetics><neoplastic cell><neuronal><neuronal survival><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><nuclear factor kappa beta><ortho-tyrosine><parkin protein><pathway><pedigree structure><phosphorylase b kinase kinase><primary degenerative dementia><protein aggregate><protein aggregation><protein homeostasis><protein kinase BRPK><protein kinase BRPK gene><proteostasis><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><senile dementia of the Alzheimer type><senior citizen><serine/threonine-protein kinase PINK1><siRNA><soluble amyloid precursor protein><spike proteins on SARS-CoV-2><suprarenal gland><tRNA Methyltransferases><transcription factor><transcriptome sequencing><transcriptomic sequencing><transmethylase><ubiquitin ligase><viral infection><viral integration><viral multiplication><viral replication><virus genome><virus infection><virus multiplication><virus protein><virus-induced disease>