Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease

Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transn...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2021-01, Vol.371 (6526)
Main Authors: Nakamura, Tomohiro, Oh, Chang-Ki, Liao, Lujian, Zhang, Xu, Lopez, Kevin M, Gibbs, Daniel, Deal, Amanda K, Scott, Henry R, Spencer, Brian, Masliah, Eliezer, Rissman, Robert A, Yates, 3rd, John R, Lipton, Stuart A
Format: Article
Language:English
Subjects:
Aberration
Aging
Aging (natural)
Alzheimer Disease - enzymology
Alzheimer Disease - pathology
Alzheimer's disease
Amyloid beta-Peptides - metabolism
Animals
Anions
Biochemistry
Brain
Cognitive ability
Cyclin-Dependent Kinase 5 - metabolism
Cyclin-dependent kinases
Cysteine
Cysteine - genetics
Cysteine - metabolism
Damage
Dementia disorders
Disease Models, Animal
Dynamins - metabolism
Enzymes
HEK293 Cells
Humans
Kinases
Mice
Mice, Transgenic
Mutation
Networks
Neurodegenerative diseases
Nitric oxide
Nitric Oxide - metabolism
Nitric Oxide Synthase - metabolism
Nitroarginine - pharmacology
Nitrogen
Nucleophiles
Oligomerization
Oxidation-Reduction
Pathogenesis
Pathology
Peptides
Protein Processing, Post-Translational - drug effects
Proteins
Reaction mechanisms
Redox reactions
Synapses
Synapses - enzymology
Synapses - pathology
Thiols
Ubiquitin Thiolesterase - genetics
Ubiquitin Thiolesterase - metabolism
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Summary:Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer's disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aaw0843