Biology subjects

Bloom, A. J.

Publications and source records attributed to Bloom, A. J..

9 recordsLinked to original sources

bioRxiv2026

Mitochondrial NAD+ import gates neuronal resilience to active SARM1

SARM1 is an inducible NADase that executes pathological axon degeneration, but how NAD+ destruction causes neuronal failure remains unclear. Because SARM1 is predicted to act outside the mitochondrial matrix, cytosolic NAD+ loss has been viewed as the critical lethal lesion. We show that SARM1 activation rapidly depletes cytosolic and mitochondrial NAD+ and collapses ATP in both compartments, revealing early, coupled metabolic failure. Enhancing mitochondrial NAD+ import through SLC25A51, the mitochondrial NAD+ transporter, preserves mitochondrial NAD+, maintains mitochondrial function, and delays axon degeneration and neuronal death despite ongoing SARM1 activity. Unexpectedly, SLC25A51 restores cytosolic NAD+-dependent metabolism, reversing a glycolytic block and increasing NAD+ synthesis during stress. Glycolytic inhibition attenuates protection, identifying cytosolic metabolic recovery as an important component of neuronal resilience. AAV-SLC25A51 improves function in a chronic SARM1-dependent neuropathy model. Thus, mitochondrial NAD+ import gates SARM1-driven degeneration by limiting coupled mitochondrial-cytosolic metabolic failure, presenting a downstream intervention point for axon preservation.

neuroscience↗

bioRxiv2026

Natural Variations of Spring Wheat Nitrogen and Carbon Assimilation under Different Inorganic Nitrogen Forms and CO2 levels

Wheat (Triticum aestivum L.) production depends upon nitrogen fertilization and may be threatened by the climate conditions anticipated in the next few decades. The natural variation in the ability of wheat to assimilate carbon and different inorganic nitrogen forms, nitrate (NO3-) and ammonium (NH4+), into vegetative growth remains unexplored. Here, we evaluated growth under either NO3- or NH4+ as a sole nitrogen source for 875 spring hexaploid wheat accessions that represent the genetic diversity within the global germplasm. These accessions varied over 8-fold in vegetative biomass but grew similarly under moderate levels of either nitrogen form. At high, potentially toxic concentrations of NH4+, however, they lost approximately 20% of their biomass. We characterized the influence of changing CO2 levels in bi-parental Nested Association Mapping populations. Genetic backgrounds determined wheat biomass responses to CO2 enrichment and nitrogen form. Genome-Wide Association and linkage mapping identified certain loci as consistently associated with biomass accumulation under different nitrogen forms and CO2 levels. These results will assist breeding efforts to develop food crops that are resilient to the worlds climate changes.

plant biology↗

bioRxiv2025

TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD

Inappropriate externalization of phosphatidylserine (PS) is a candidate mechanism of pathogenic neuroinflammation, a critical driver of neurodegenerative disease. ATP8A2, a flippase that maintains PS on the plasma membrane inner leaflet, is mutated in both Wabbler-lethal mice and patients with the ataxia syndrome CAMRQ4. Here, we identify ATP8A2 as a target of TDP-43 cryptic exon suppression, and demonstrate that ATP8A2 loss leads to immune-mediated neurodegeneration. ATP8A2 splicing is significantly dysregulated following TDP-43 depletion in human neurons and in brains of patients with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In mice, Atp8a2 loss increases PS exposure and promotes neuroinflammation. Depletion of peripheral macrophages rescues motor axon degeneration and doubles Atp8a2 knockout mouse lifespan, while depletion of both peripheral macrophages and central microglia quadruples lifespan and improves coordination. Hence, ATP8A2 is a pathologically relevant TDP-43 target and inhibition of phagocytic immune cell attack against neurons is a potential treatment for patients with CAMRQ4 and ALS-FTD.

neuroscience↗

bioRxiv2024

Genome-wide Association Study of Rice Vegetative Biomass under Different Inorganic Nitrogen Forms: Ammonium or Nitrate

Rice is the most important source of daily calories in human diets and second only to wheat as the most important protein source. Rice is generally exposed to high ammonium (NH4+) levels in the rhizosphere but may employ both NH4+ and nitrification-derived nitrate (NO3-) as major sources of nitrogen. However, the genetic basis underlying rice adaptation to different nitrogen forms remains poorly characterized. Here, we assessed biomass under either NH4+ or NO3- as a sole nitrogen source in 390 accessions from the USDA Rice Diversity Panel 1. Rice effectively used either form of nitrogen to support early growth. Tolerance to a high-NH4+ exposure was correlated with biomass under NO3- and lower NH4+ levels. Both genotype and nitrogen source strongly influenced biomass accumulation and partitioning between shoot and root. Root showed the greatest biomass variability and sensitivity to nitrogen source. Genome-wide analyses identified 176 single nucleotide polymorphism (SNP) markers associated with biomass across the full diversity panel and individual populations. The majority of the associations were unique to the individual nitrogen source. We compiled a list of candidate genes, including putative genes involved in nitrogen metabolism, located within 150 kb of 112 most significant SNPs, each with at least 3 adjacent markers detected under the same combination of population and nitrogen source. A flexible consumer, rice may employ distinct genetic mechanisms to use different nitrogen sources, making the species more resilient to fluctuations in soil nitrogen. These insights can guide matching rice genotypes with fertilizer management to improve nitrogen-use efficiency.

plant biology↗

bioRxiv2024

Rubisco from two ecotypes of Plantago lanceolata L. that are native to sites differing in atmospheric CO2 levels

Rubisco, the most prevalent protein on the planet, initiates the conversion of CO2 into carbohydrates during photosynthesis. Responses of this process to atmospheric CO2 fluctuations daily, seasonally, and over millennia is still poorly understood. We have hypothesized that higher plants maintain carbon-to-nitrogen homeostasis by adjusting the balance of magnesium and manganese in chloroplasts to alter their relative carbon fixation and nitrogen assimilation rates. The following study examined the influence of magnesium and manganese on rubisco carboxylation and oxygenation in protein purified from two ecotypes of Plantago lanceolata: one adapted to the high atmospheric CO2 that occurs near a natural CO2 spring and the other adapted to more typical CO2 atmospheres that occur nearby. The plastid DNA coding for the large unit of rubisco were similar in both ecotypes. The kinetics of rubiscos from the two ecotypes differed more when they were associated with manganese than magnesium. Specificity for CO2 over O2 (Sc/o) for rubiscos from both ecotypes were higher when the enzymes were bound to magnesium than manganese. This disparity may account for the adaptation of this species to different CO2 environments.

plant biology↗

bioRxiv2024

Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves

Programmed axon degeneration (AxD) is a key feature of many neurodegenerative diseases. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of AxD, preventing it from initiating the rapid local NAD+ depletion and metabolic catastrophe that precipitates axon destruction. Because these components of the AxD pathway act within neurons, it was also assumed that the timetable of AxD was set strictly by a cell-intrinsic mechanism independent of neuron-extrinsic processes later activated by axon fragmentation. However, using a rare human disease model of neuropathy caused by hypomorphic NMNAT2 mutations and chronic SARM1 activation (sarmopathy), we demonstrated that neuronal SARM1 can initiate macrophage-mediated axon elimination long before stressed-but-viable axons would otherwise succumb to cell-intrinsic metabolic failure. Investigating potential SARM1-dependent signals that mediate macrophage recognition and/or engulfment of stressed-but-viable axons, we found that chronic SARM1 activation triggers axonal blebbing and dysregulation of phosphatidylserine (PS), a potent phagocyte immunomodulatory molecule. Neuronal expression of the phosphatidylserine lipase ABDH12 suppresses nerve macrophage activation, preserves motor axon integrity, and rescues motor function in this chronic sarmopathy model. We conclude that PS dysregulation is an early SARM1-dependent axonal stress signal, and that blockade of phagocytic recognition and engulfment of stressed-but-viable axons could be an attractive therapeutic target for management of neurological disorders involving SARM1 activation.

neuroscience↗

bioRxiv2023

Genetic adaptation to ammonium sustains wheat grain quality and alleviates acclimation to CO2 enrichment

Plants synthesize protein through assimilating inorganic nitrogen. Yet, the extent to which soil nitrogen sources alter crop responses to atmospheric CO2 remains uncertain. We assessed wheat (Triticum aestivum L.) biomass under CO2 enrichment in genotypes that demonstrated a preference for ammonium (NH4+) or nitrate (NO3-), and contrasting degrees of NH4+ tolerance. Nitrogen-form preference, but not NH4+ tolerance, correlated with CO responses. Notably, NH4+-preferring genotypes maintained higher biomass and sustained grain nitrogen concentrations, thus avoiding CO2 acclimation, the decline in biomass stimulation after prolonged exposure to CO2 enrichment. Furthermore, NH4+ nutrition accelerated flowering and increased spike biomass. Breeding for NH4+-adapted genotypes may not only improve climate resilience, but also potentially accelerate development and increase yield without any penalty on grain quality. Because wheat provides 20% of the protein and carbohydrate in the human diet, our study provided strategies to sustain food security under the atmospheric conditions anticipated in the future. HighlightBreeding for NH4+-adapted genotypes may not only improve climate resilience, but also potentially accelerate development and increase yield without any penalty on grain quality under elevated CO2 atmospheres.

plant biology↗

bioRxiv2022

Differential genetic variation underlying Ammonium and Nitrate responses in Arabidopsis thaliana

Nitrogen is an essential element required for plant growth and productivity. Understanding the mechanisms and natural genetic variation underlying nitrogen use in plants will facilitate engineering plant nitrogen use to maximize crop productivity while minimizing environmental costs. To understand the scope of natural variation that may influence nitrogen use, we grew 1135 Arabidopsis thaliana natural genotypes on two nitrogen sources, nitrate and ammonium, and measured both developmental and defense metabolite traits. By using different environments and focused on multiple traits, we identified a wide array of different nitrogen responses. These responses are associated with a large number of genes, most of them not previously associated with nitrogen responses. Only a small portion of these genes appear to be shared between environments or traits while most of the detected genes are predominantly specific to a developmental or defense trait under a specific nitrogen source. Finally, by using a large population we were able to identify unique nitrogen responses, like preferring ammonium or nitrate, that appear to be generated by combinations of loci rather than a few large effect loci. This suggests that it may be possible to obtain novel phenotypes in complex nitrogen responses by manipulating sets of genes with small effects rather than solely focusing on large effect single gene manipulations. One Sentence SummaryUsing a large collection of natural genotypes, and studying both developmental and metabolic responses, we found a large number of genes that are involved in the plants nitrogen response.

plant biology↗

bioRxiv2022

Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

TDP-43 mediates proper Stathmin-2 (STMN2) mRNA splicing, and STMN2 protein is reduced in the spinal cord of most ALS patients. To test the hypothesis that STMN2 loss contributes to ALS pathogenesis, we generated constitutive and conditional STMN2 knockout mice. Constitutive STMN2 loss results in early-onset sensory and motor neuropathy featuring impaired motor behavior and dramatic distal neuromuscular junction (NMJ) denervation of fast-fatigable motor units, which are selectively vulnerable in ALS, without axon or motoneuron degeneration. Selective excision of STMN2 in motoneurons leads to similar NMJ pathology. STMN2 KO heterozygous mice, which better model the partial loss of STMN2 protein found in ALS patients, display a slowly progressive, motor-selective neuropathy with functional deficits and NMJ denervation. Thus, our findings strongly support the hypothesis that STMN2 reduction due to TDP-43 pathology contributes to ALS pathogenesis.

neuroscience↗