Biology subjects

Enriquez, A.

Publications and source records attributed to Enriquez, A..

7 recordsLinked to original sources

bioRxiv2026

NMNAT2-SARM1 Axis Drives Redox Failure and Disrupts APP Processing in Neurons

Metabolic dysfunction and proteinopathy are hallmarks of many neurodegenerative diseases, yet their mechanistic interplay remains poorly understood. Here, we demonstrate that amyloid precursor protein (APP) processing in cortical neurons is disrupted upon loss of Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), the NAD-synthesizing enzyme in neurons, resulting in accumulation of APP C-terminal fragments (APP-CTFs). Knockdown (KD) of the NAD hydrolase sterile alpha and TIR motif-containing protein 1 (SARM1) restores APP-CTF levels in NMNAT2 knockout (KO) neurons to wild-type levels, whereas NAD supplementation yields modest rescue. Redox profiling indicates that NMNAT2 loss reduces NAD/NADH redox potential when APP-CTF starts accumulating. Seahorse metabolic flux analysis shows that NMNAT2 deficiency induces early glycolytic impairment, followed by deficits in mitochondrial respiration. Notably, SARM1 KD, but not NAD supplementation, rescues mitochondrial function in NMNAT2 KO neurons. Temporal profiling of NMNAT2 KO neurons revealed a biphasic pattern in APP-CTF accumulation, with an initial gradual increase followed by a marked acceleration, paralleling the transition from an initially small number to a substantially greater number of differentially expressed proteins. Pathway enrichment analysis of proteomic changes suggests JNK/MAPK signaling is upregulated in the early phase, with late-phase downregulation of mitochondrial function and upregulation of endoplasmic reticulum stress and unfolded protein response pathways. Collectively, these findings demonstrate that neuronal NAD depletion drives a progressive, SARM1-dependent disruption of redox homeostasis and proteostasis, resulting in impaired APP processing. The NMNAT2-SARM1 axis emerges as a critical pathway linking metabolic stress to proteinopathy, positioning SARM1 as a key mediator of neurodegenerative dysfunction.

neuroscience↗

bioRxiv2025

NAD+ reduction in glutamatergic neurons triggers fatty acid catabolism and neuroinflammation in the brain, mitigated by SARM1 deletion

The importance of NAD+ homeostasis for neuronal health has been emphasized by studies on nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2), a NAD+-synthesizing enzyme, and sterile alpha and TIR motif-containing protein 1 (SARM1), a NAD+ hydrolase. NMNAT2 declines caused by neurodegenerative insults activate SARM1 to degenerate axons. To elucidate the impact of the NMNAT2-SARM1 axis on brain energy metabolism, we employed multi-omics approaches to investigate the metabolic effects caused by neuronal NMNAT2 loss. The loss of NMNAT2 in glutamatergic neurons results in a striking metabolic shift in the cerebral cortex from glucose to lipid catabolism, reduced lipid abundance, and pronounced neurodegenerative phenotypes. Proteomic analysis found that neuronal NMNAT2 loss altered levels of glial enzymes central to glucose and lipid metabolism. Genetic deletion of SARM1 in NMNAT2-deficient mice restores lipid metabolism and mitigates neurodegeneration. Taken together, we show that neuronal NAD+ reduction leads to SARM1-dependent maladaptive adaptations in both neurons and glia.

neuroscience↗

bioRxiv2024

Temporal dynamics of inflammatory and transcriptome changes in the myocardium in a murine model of cardiac arrest

BackgroundIt is increasingly recognized that inflammatory changes play a significant role in myocardial injury following cardiac arrest. However, the pathophysiological mechanisms responsible for functional changes in the myocardium following the event remain incompletely understood. Here, we characterize the transcriptomic and immunological changes in a mouse model of cardiac arrest to explore the roles of epinephrine and ischemia/reperfusion on myocardial inflammation. Methods and ResultsMale and female mice (C57BL/6J) were divided into three groups: (1) Naive (anesthesia only), (2) Sham (anesthesia + saline injection + epinephrine), and (3) Arrest (8-minute cardiac arrest followed by resuscitation (anesthesia + potassium chloride + epinephrine). We monitored the animals over 0.5, 1, 3, and 7 days with serial echocardiography. Hearts were harvested for transcriptomic analysis and inflammatory changes as assessed by flow cytometry and immunohistochemistry. Plasma samples were collected for cytokine signaling analysis by multiplex ELISA. Our data indicate that the cardiac arrest group have increased infiltrating neutrophils in the myocardium and elevated plasma levels of pro-inflammatory cytokines, peaking at 0.5 days after the initial insult and subsequently resolving. In contrast, Sham mice displayed less pronounced inflammatory changes, which peaked at 1 day after the procedure. Notably, these inflammatory alterations coincided with cardiac stunning, as demonstrated by echocardiography. ConclusionsIn our murine model of cardiac arrest, epinephrine exposure and ischemia/reperfusion induce significant inflammatory changes in the myocardium with increased infiltrating neutrophils and elevated circulating cytokines which subsequently resolve in a time-dependent manner. These changes correlate with improving cardiac function by echocardiography.

immunology↗

bioRxiv2023

Characterization of Ralstonia pseudosolanacearum diversity and screening host resistance to manage bacterial wilt in South Asia

In South Asia, bacterial wilt pathogens in the Ralstonia solanacearum species complex (RSSC) impose major constraints on eggplant, tomato, and pepper production. To improve the efficacy of bacterial wilt management, the goals of this study were to (1) conduct a survey of RSSC pathogens in Bangladesh and Nepal, (2) characterize the genetic diversity of these isolates, and (3) screen 37 tomato, eggplant, and pepper accessions for resistance to six representative isolates from South Asia. We isolated 99 isolates from Bangladesh and 20 isolates from Nepal and determined that all are phylotype I isolates of the Ralstonia pseudosolanacearum species. We sequenced and assembled draft genomes for 25 isolates. Phylogenomic analyses suggest that there is a wide diversity of endemic phylotype I isolates in South Asia, and possible introductions of two clonal phylotype I lineages into Bangladesh and Nepal. We contextualize our newly described isolates based on prior reports of RSSC diversity in South Asia and global reports of RSSC pathogens on eggplant and pepper. Greenhouse trials revealed multiple tomato, eggplant, and pepper accessions that exhibit promising levels of resistance to six phylotype I isolates from South Asia.

microbiology↗

bioRxiv2023

Seafloor Incubation Experiments at Deep-Sea Hydrothermal Vents Reveal Distinct Biogeographic Signatures of Autotrophic Communities

The discharge of hydrothermal vents on the seafloor provides energy sources for dynamic and productive ecosystems, which are supported by chemosynthetic microbial populations. These populations use the energy gained by oxidizing the reduced chemicals contained within the vent fluids to fix carbon dioxide and support multiple trophic levels. Hydrothermal discharge is ephemeral and chemical composition of such fluids varies over space and time, which can result in geographically distinct microbial communities. To investigate the foundational members of the community, microbial growth chambers were placed within the hydrothermal discharge at Axial Seamount (Juan de Fuca Ridge), Magic Mountain Seamount (Explorer Ridge), and Kamaehuakanaloa Seamount (Hawaii hotspot). Campylobacteria were identified within the nascent communities, but different amplicon sequence variants were present at Axial and Kamaehuakanaloa Seamounts, indicating that geography in addition to the composition of the vent effluent influences microbial community development. These results provide insights to nascent microbial community structure and shed light on the development of diverse lithotrophic communities at hydrothermal vents.

microbiology↗

bioRxiv2023

Characterising genome composition and large structural variation in banana varietal groups

BackgroundBananas and plantains (Musa spp.) are one of the most important crops worldwide. The cultivated varieties are vegetatively propagated, and their diversity is essentially fixed over time. Nevertheless, millennia of diversification and selection have led to hundreds of edible varieties. M. acuminata and M. balbisiana respectively provided the A and B subgenomes that mostly constitute these varieties. Here we aimed to characterise chromosomal exchanges and structural variation among lineages to understand shared foundational events and identify sources of allelic diversity in introgressed loci for genetic improvement. MethodsWe identified clonal somatic groups among 188 banana and plantain accessions introduced for cropping in Colombia, using admixture, principal component, and phylogenetic analyses. We established a new alignment-based metric, named Relative Averaged Alignment (RAA), to infer subgenome composition (AA, AAB, etc.). We later used comparisons in read coverage along conserved chromosomal windows between the A, B, and S subgenomes to identify introgressions. ResultsIn our panel, we identify ten varietal groups composed of somatic clones, plus three groups of tetraploid accessions. We demonstrated RAA can be used to infer subgenome composition in the total genome and individual chromosomes. We identified 20 introgressions, several newly reported, among the AAB and ABB varieties. We did not observe B-donor introgression in any AA/AAA varietal groups. We identified variation in length in at least two introgressions, a B-donor introgression in chromosome 7 between the "Maoli" and a "Popoulu" subdivisions, and an S-donor (M. schizocarpa) introgression in chromosome 2 in four varietal groups with different compositions (AAA, AAB, ABB, and AA). ConclusionsThe extensive distribution of introgressions and the variation in the length of some introgressions between varieties support that the emergence of many varieties can be attributed to intricate founding events, which encompassed multiple instances of hybridisation and subsequent residual backcrossing. We also showed the contribution of M. schizocarpa to four cultivated varieties, and proposed subdivision-specific intergenomic recombination in chromosome 7 between subgroups Maoli and Popoulu plantains. Introgressed loci over these 20 introgressions likely provide an extensive resource of allelic diversity to further explore their contribution to disease resistance, climatic adaption, etc. and potential for exploiting in breeding and genome editing.

plant biology↗

bioRxiv2022

NMNAT2 is the major NAD+ provider for vesicular glycolysis generating on-board energy for fast axonal transport cargos

BackgroundBioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimers, Parkinsons and Huntingtons disease. Here we addressed whether NMNAT2 is required for axonal health of cortical glutamatergic neurons, whose far-projecting axons are vulnerable to neurodegenerative conditions. We also tested if NMNAT2 maintains axonal health by ensuring proper axonal ATP levels for axonal transport, a critical function of axons. MethodsWe generated mouse and cultured neuron models to determine the impact of NMNAT2 loss from cortical glutamatergic neurons on axonal transport, energetic metabolism, and morphological integrity. In addition, we determined if exogenous NAD supplementation or inhibiting NAD hydrolase sterile alpha and TIR motif-containing protein 1 (SARM1) prevented axonal deficits caused by NMNAT2 loss. Our study used a combination of genetic, molecular biology, immunohistochemistry, biochemistry, fluorescent time-lapse imaging, live imaging with optical sensors, and anti-sense oligos application. ResultsWe provide in vivo evidence that NMNAT2 in cortical glutamatergic neurons is required for axonal survival. Using in vivo and in vitro studies we demonstrate that NMNAT2 protects axons by ensuring the proper NAD-redox potential in distal axons of cortical neurons to support glycolysis on vesicular cargos, thus ensuring "onboard" ATP production fueling axonal transport. Exogenous NAD+ supplementation to NMNAT2 KO cortical neurons restores glycolysis and resumes fast axonal transport. Finally, we demonstrate both in vitro and in vivo that reducing the activity of SARM1, an NAD degradation enzyme, can reduce axonal transport deficits and suppress axon degeneration in NMNAT2 KO neurons. ConclusionNMNAT2 ensures axonal health by maintaining NAD redox potential in distal axons to ensure efficient vesicular glycolysis required for fast axonal transport.

neuroscience↗