Prefrontal cortex and depression

Neuropsychopharmacology, Год журнала: 2021, Номер 47(1), С. 225 - 246

Опубликована: Авг. 2, 2021

Язык: Английский

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Evolving concepts in NAD+ metabolism

Cell Metabolism, Год журнала: 2021, Номер 33(6), С. 1076 - 1087

Опубликована: Апрель 29, 2021

Язык: Английский

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Central nervous system regeneration

Cell, Год журнала: 2022, Номер 185(1), С. 77 - 94

Опубликована: Янв. 1, 2022

Язык: Английский

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A genetic map of the mouse dorsal vagal complex and its role in obesity

Nature Metabolism, Год журнала: 2021, Номер 3(4), С. 530 - 545

Опубликована: Март 25, 2021

Язык: Английский

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Shared TIR enzymatic functions regulate cell death and immunity across the tree of life

Science, Год журнала: 2022, Номер 377(6605)

Опубликована: Июль 7, 2022

In the 20th century, researchers studying animal and plant signaling pathways discovered a protein domain that is shared across diverse innate immune systems: Toll/interleukin-1/resistance gene (TIR) domain. The TIR found in several architectures was defined as an adaptor mediates protein-protein interactions immunity developmental pathways. However, studies of nerve degeneration animals-and subsequent breakthroughs plant, bacterial, archaeal systems-revealed domains possess enzymatic activities. We provide synthesis functions role various related products evolutionarily systems. These may ultimately guide interventions would span tree life, from treating human neurodegenerative disorders bacterial infections to preventing diseases.

Язык: Английский

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Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling

Science, Год журнала: 2022, Номер 377(6614)

Опубликована: Сен. 1, 2022

Cyclic adenosine diphosphate (ADP)–ribose (cADPR) isomers are signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via nicotinamide adenine dinucleotide (oxidized form) (NAD + ) hydrolysis. We show that v-cADPR (2′cADPR) v2-cADPR (3′cADPR) cyclized O-glycosidic bond formation between the ribose moieties in ADPR. Structures of 2′cADPR-producing TIR reveal conformational changes lead to an active assembly resembles those Toll-like adaptor domains. Mutagenesis reveals a conserved tryptophan is essential for cyclization. 3′cADPR activator ThsA effector proteins from antiphage defense system termed Thoeris suppressor immunity when HopAM1. Collectively, our results molecular basis cADPR isomer production establish bacteria as antiviral immunity–suppressing molecule.

Язык: Английский

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Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules

Molecular Cell, Год журнала: 2022, Номер 82(9), С. 1643 - 1659.e10

Опубликована: Март 25, 2022

The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration therapeutic target for several neurodegenerative conditions. We show that potent inhibitor undergoes base exchange with the nicotinamide moiety adenine dinucleotide (NAD

Язык: Английский

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Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Янв. 6, 2022

Abstract Background In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD + hydrolase, SARM1. healthy SARM1 is autoinhibited, but single amino acid changes can abolish autoinhibition leading constitutively active enzymes that promote degeneration when expressed in cultured neurons. Methods To investigate whether naturally occurring human variants might disrupt and potentially contribute risk for neurodegenerative disease, we assayed enzymatic activity all 42 rare alleles identified among 8507 amyotrophic lateral sclerosis (ALS) patients 9671 controls. We then intrathecally injected mice with virus expressing constructs test capacity an ALS-associated variant neurodegeneration vivo. Results Twelve out missense or small in-frame deletions exhibit constitutive NADase activity, including more than half those are unique ALS occur multiple patients. There > 5-fold enrichment compared Expression dorsal root ganglion (DRG) pro-degenerative cytotoxic. Intrathecal injection AAV common reference allele innocuous mice, construct harboring V184G , found most frequently patients, causes loss, motor dysfunction, sustained neuroinflammation. Conclusions These results implicate hypermorphic as candidate genetic factors other conditions.

Язык: Английский

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Structural basis of NLR activation and innate immune signalling in plants

Immunogenetics, Год журнала: 2022, Номер 74(1), С. 5 - 26

Опубликована: Янв. 4, 2022

Abstract Animals and plants have NLRs (nucleotide-binding leucine-rich repeat receptors) that recognize the presence of pathogens initiate innate immune responses. In plants, there are three types distinguished by their N-terminal domain: CC (coiled-coil) domain NLRs, TIR (Toll/interleukin-1 receptor) RPW8 (resistance to powdery mildew 8)-like coiled-coil NLRs. CC-NLRs (CNLs) TIR-NLRs (TNLs) generally act as sensors effectors secreted pathogens, while RPW8-NLRs (RNLs) signal downstream many sensor called helper Recent studies revealed dimensional structures a CNL (ZAR1) including its inactive, intermediate active oligomeric state, well TNLs (RPP1 ROQ1) in states. Furthermore, accumulating evidence suggests members family lipase-like EDS1 (enhanced disease susceptibility 1) proteins, which uniquely found seed play key role providing link between during Here, we summarize implications plant NLR provide insights into distinct mechanisms action different discuss NLR-mediated signalling pathways involving proteins RNLs.

Язык: Английский

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Molecular innovations in plant TIR-based immunity signaling

The Plant Cell, Год журнала: 2022, Номер 34(5), С. 1479 - 1496

Опубликована: Фев. 4, 2022

Abstract A protein domain (Toll and Interleukin-1 receptor [TIR]-like) with homology to animal TIRs mediates immune signaling in prokaryotes eukaryotes. Here, we present an overview of TIR evolution the molecular versatility domains different architectures for host protection against microbial attack. Plant TIR-based emerges as being central potentiation effectiveness defenses triggered by intracellular cell-surface receptors. Equally relevant plant fitness are mechanisms that limit potent healthy tissues but maintain preparedness infection. We propose seed plants evolved a specialized module selectively translate enzymatic activities defense outputs, overlaying more general function TIRs.

Язык: Английский

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