Biology subjects

Rai, M.

Publications and source records attributed to Rai, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Metabolic and transcriptional responses reveal co-option of symbiotic processes during early soybean-soybean cyst nematode interaction

The biochemical mechanisms by which virulent populations of soybean cyst nematode (Heterodera glycines, SCN) overcome host resistance are critical to understanding this economically important pathogen. Here, we deployed metabolic and transcriptome profiling of soybean roots during the SCN infection and establishment process to investigate the molecular and biochemical mechanisms of pathogen establishment. Across samples from a time series spanning nematode invasion to syncytium maturation, we demonstrate that compatible SCN infection does not bypass host immunity but systematically remodels it. In a compatible interaction between soybean carrying the high-copy Rhg1 resistance locus challenged with HG Type 2.5.7 SCN virulent on this host, we identify a 72-metabolite defense signature spanning isoflavonoids, triterpenoid saponins, and phenylpropanoids that persist across all infection stages. Despite activation of this metabolic defense signature by the pathogen on infection, defense transcription is near silence by 3 days post-infection, while defense metabolites persist, revealing a critical decoupling of transcriptional and metabolic defense programs at the precise window of syncytium initiation. Suppression of phenylpropanoid accumulation occurs downstream of PAL transcription, indicating a block at the metabolic level invisible to transcriptomics alone. By 5 days post-infection, cytokinin accumulation coincides with nodulin gene induction and phospholipid remodeling consistent with activation of the legume symbiosis program during syncytium maturation. Together, these findings establish that compatibility arises not from failed recognition but from progressive immune dismantling, including suppression of defense chemistry and co-option of the legume-rhizobium symbiosis machinery.

plant biology↗

bioRxiv2026

Drosophila melanogaster lactate dehydrogenase deficiency recapitulates the exercise intolerance of human glycogen storage disease type XI

Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme that commonly exhibits altered expression in human diseases such as cancers and neurodegeneration, making it a valuable disease biomarker and putative therapeutic target. However, any treatment targeting LDHA will also disrupt normal metabolism, underscoring the need to investigate physiological consequences of inhibiting this enzyme. We previously established the fruit fly Drosophila melanogaster as a genetic model for studying LDH function in the context of growth, metabolism, and development. Here we expand upon those studies by investigating a serendipitous observation that Ldh mutant larvae exhibit diet-dependent lethality. Using a multiomic approach, we discovered this diet-dependent phenotype is independent of nutritional composition. Instead, Ldh mutant larvae are exercise intolerant and display reduced mobility, rendering mutant larvae sensitive to food consistency. Moreover, tissue-specific analysis reveals that LDH activity within muscle and peripheral glia are essential for larval viability raised on solid food. Intriguingly, these phenotypes mirror the pathophysiology of LDHA deficiency (Glycogen Storage Disease Type XI; GSD Type XI) in humans, where mild symptoms are exacerbated by physical exertion and environmental stress. Together, our findings further highlight the value of using Drosophila to explore the developmental and physiological consequences of Ldh inhibition. SUMMARY STATEMENTLoss of lactate dehydrogenase in Drosophila causes exercise intolerance and diet-dependent lethality, revealing conditional phenotypes that mirror those associated with human LDH-A deficiency.

developmental biology↗

bioRxiv2025

New alleles of D-2-hydroxyglutarate dehydrogenase enable studies of oncometabolite function in Drosophila melanogaster

D-2-hydroxyglutarate (D-2HG) is a potent oncometabolite capable of disrupting chromatin architecture, altering metabolism, and promoting cellular dedifferentiation. As a result, ectopic D-2HG accumulation induces neurometabolic disorders and promotes progression of multiple cancers. However, the disease-associated effects of ectopic D-2HG accumulation are dependent on genetic context. Specifically, neomorphic mutations in the mammalian genes Isocitrate dehydrogenase 1 (IDH1) and IDH2 result in the production of enzymes that inappropriately generate D-2HG from -ketoglutarate (KG). Within this genetic background, D-2HG acts as an oncometabolite and is associated with multiple cancers, including several diffuse gliomas. In contrast, loss-of-function mutations in the gene D-2-hydroxyglutarate dehydrogenase (D2hgdh) render cells unable to degrade D-2HG, resulting in excessive buildup of this molecule. D2hgdh mutations, however, are not generally associated with elevated cancer risk. This discrepancy raises the question as to why ectopic D-2HG accumulation in humans induces context-dependent disease outcomes. To enable such genetic studies in vivo, we generated two novel loss-of-function mutations in the Drosophila melanogaster gene D2hgdh and validated that these alleles result in ectopic D-2HG. Moreover, we observed that D2hgdh mutations induce developmental and metabolomic phenotypes indicative of elevated D-2HG accumulation. Overall, our efforts provide the Drosophila community with new mutant strains that can be used to study D-2HG function in human disease models as well as in the context of normal growth, metabolism, and physiology.

genetics↗

bioRxiv2025

Consistency in floral volatiles impacts plant-pollinator interactions in the face of environmental change in the Eastern Himalayas

Floral scents are an important mediator of many plant-pollinator interactions. However, environmental and ecological change could affect the synthesis and emission of volatile chemicals that constitute floral scents, potentially influencing pollinator perception of scents. We investigated the effects of elevation and warming on the floral scents of multiple co-occurring alpine meadow plant species along an elevational gradient in the Eastern Himalayas (3000 - 4000 masl). We also investigated pollinator responses in the same locations using 3-D printed floral models that replicated the differing volatile constituents. Finally, we assessed how pollinator preferences changed with variations in elevation, flowering season and location. We found that elevation and in-situ warming using Open Top Chambers (OTC) led to significant intraspecific variation in the composition of floral scents, both in terms of quality and quantity of volatiles released. Nevertheless, conspecific floral scents across elevations were more similar to each other than to other species. Cafeteria assays using artificial floral models revealed that pollinator preferences were driven by a small number of volatiles (p-cymene, 2-pentylfuran and -pinene), but these preferences were abolished in a novel plant-pollinator community where the same floral volatiles were not detected. Our results suggest that the local odourscape established by the floral community present plays a key role in plant-pollinator interactions. This emphasizes the need to incorporate ecological impacts such as changes in community into climate change analyses to understand the long-term impacts of human activity on co-evolutionary relationships like pollination. Significance StatementFloral scents are important for most plant-pollinator interactions, and can be affected by environmental factors like elevation and temperature. Our study shows that elevation and simulated in situ warming change the composition of floral scents, yet scents from the same species were more similar to each other across elevations and temperatures than to other species. Further, pollinator preferences to these scents replicated in artificial models persisted in spite of variation in temperature and elevation, but not in a novel plant-pollinator community containing floral species not releasing those volatiles. This emphasizes the need to incorporate factors such as floral community composition into our understanding of the long-term impacts of climate change and human activity on co-evolutionary relationships like pollination.

ecology↗

bioRxiv2025

Laboratory adaptive evolution of thermotolerance is linked to the evolution of a robust proteostasis in S. cerevisiae

Thermophilic organisms have evolved a proteome that resists thermal denaturation. While the evolution of their complete proteome would require multiple generations, early on, organisms would need to develop strategies to survive at high temperatures despite their thermolabile proteome. We hypothesized that the organisms would do this by reinforcing their proteostasis capacity. We tested this hypothesis using adaptive laboratory evolution of thermotolerance in Saccharomyces cerevisiae and found that the cells reproducibly evolved better proteostasis capacity in short-term evolution experiments. However, rather than improving the global proteostasis capacity, most of the evolved strains demonstrated enhanced capacity to tackle misfolding in the Endoplasmic Reticulum (ER), specifically by increasing their capacity for ER-associated degradation (ERAD). Given the strong selective advantage of these strains, we posit that protein folding in the ER may be exquisitely sensitive to chronic thermal stress and may act as an early indicator for adaptation to higher temperatures.

evolutionary biology↗

bioRxiv2024

Vocal species are more central in Eastern Himalayan Mixed-Species bird flocks

Mixed-species flocks (MSF) represent an important form of social organisation in bird communities worldwide. Despite its likely importance in flock formation and cohesion, the role of vocal communication in the formation and maintenance of MSF in birds is hitherto understudied. In this study, we examine if a species centrality within a mixed-species flock is influenced by its vocal behaviour during the dawn chorus, i.e., the time of MSF formation. Using acoustic sampling and field observations, we studied the bird species found in MSF in the Eastern Himalayas. Our results show differential vocal activity patterns among MSF-forming bird species and suggest a positive correlation between calling rates and closeness centrality (species importance in a flock) in understory MSFs. We also found a more synchronised vocalisation pattern in the understory MSFs, with a consistent peak in vocal activity in the early morning hours, whereas no consistent vocal pattern was found for canopy flocks. Overall, our results suggest a potential mechanism that drives MSF formation wherein the vocal activity of central species precedes and likely attracts participation from other attendant species.

ecology↗

bioRxiv2024

Fitness defects due to cytosolic protein misfolding in S. cerevisiae can be alleviated by decreasing mitochondrial protein import capacity

Protein misfolding affects cellular fitness. This can be caused due to the toxic aggregation of one species of protein or global protein misfolding events. Since the fitness defect arises due to the multi-modal effect of misfolding, there is no consensus mechanism to alleviate this fitness defect. Here, we used adaptive laboratory evolution of thermotolerance to identify pathways contributing to proteotoxic stress resistance in S. cerevisiae. Our results suggest a link between thermotolerance and proteotoxicity resistance, majorly routed through the loss of mitochondrial DNA. Loss of mitochondrial DNA decreased the association of mistargeted misfolded proteins on the mitochondrial surface and altered the cellular response to proteostasis to enhance protein quality control associated degradation. We show that a decrease in the abundance of import channels is sufficient to mimic the loss of mtDNA and increase cellular proteostasis. Thus, we uncover a cryptic interorganellar cooperation in combating proteotoxicity in yeast.

molecular biology↗

bioRxiv2024

Autoimmunity and clinical pathology amelioration in SLE by Dexamethasone primed Mesenchymal Stem Cell derived conditioned media

This study proposes a novel approach, utilizing cell-free dexamethasone (Dex) primed Whartons jelly mesenchymal stem cells derived conditioned media (DW), offering improved efficacy, simplicity, and alternative medicine for addressing complications associated with systemic lupus erythematosus (SLE). This study explores the immunomodulatory effects of DW treatment on immune cell populations in SLE patients and a pristane-induced lupus (PIL) mouse model. DW induces significant expansion of Tregs, Bregs, suppressing Th17, double-negative T cells, and inflammatory neutrophils through modulating IL-10 and IL-17A production. Comparisons with the standard drug hydroxychloroquine reveal similar effects, suggesting TGF beta; pathway mediation in DWs actions. Compared with the immunosuppressive drug Dex, DW better attenuated autoantibody production, increased anti-inflammatory cytokines and maintained a balanced Th17/Treg ratio. In the preclinical in vivo studies, DW exhibits therapeutic efficacy, reducing mortality, preventing proteinuria, and reversing limb inflammation, seizure and alopecia. Organ specific evaluations using advanced live imaging or histopathological analysis highlighted DWs protective effects on kidneys, liver, lungs, heart, and spleen. This provided insight into the immunomodulatory benefits of DW at various levels and suggested that it could be a potential therapeutic avenue for managing complications related to SLE.

immunology↗

bioRxiv2024

Glycolytic Disruption Triggers Interorgan Signaling to Nonautonomously Restrict Drosophila melanogaster Larval Growth

Drosophila larval growth requires efficient conversion of dietary nutrients into biomass. Lactate Dehydrogenase (Ldh) and Glycerol-3-phosphate dehydrogenase (Gpdh1) support larval biosynthetic metabolism by maintaining NAD+/NADH redox balance and promoting glycolytic flux. Consistent with the cooperative functions of Ldh and Gpdh1, the loss of both enzymes, but neither single enzyme, induces a developmental arrest. However, Ldh and Gpdh1 exhibit complex and often mutually exclusive expression patterns, suggesting that the Gpdh1; Ldh double mutant lethal phenotype could be mediated nonautonomously. Here we find that the developmental arrest displayed by the double mutants extends beyond simple metabolic disruption and instead stems, in part, from changes in systemic growth factor signaling. Specifically, we demonstrate that this synthetic lethality is linked to the upregulation of Upd3, a cytokine involved in the Jak/Stat signaling pathway. Moreover, we demonstrate that either loss of the Upd3 or dietary administration of the steroid hormone 20-hydroxyecdysone (20E) rescue the synthetic lethal phenotype of Gpdh1; Ldh double mutants. Together, these findings demonstrate that metabolic disruptions within a single tissue can nonautonomously modulate interorgan signaling to ensure synchronous developmental growth. SUMMARY STATEMENTWe used the fruit fly Drosophila melanogaster to demonstrate that disruption of glycolysis within a single larval tissue alters systemic cytokine signaling and nonautonomously inhibits development of the entire animal.

developmental biology↗

bioRxiv2023

Cortical F-actin filament organization corrals E-cadherin/HMR-1 during cytokinetic furrow ingression in C. elegans embryos

In metazoan cells, the delicate equilibrium between proliferative cell division and inter-cellular adhesion is crucial for achieving growth while maintaining tissue integrity and homeostasis. The transmembrane adhesion receptor, E-cadherin, not only facilitates cell-cell adhesion but modulates cytokinesis by impeding cortical F-actin flow and inhibiting actomyosin contractility. In the C. elegans zygote, newly established cell-cell interfaces following cytokinesis lack E-cadherin/HMR-1 (Padmanabhan et al., 2017b). The mechanisms responsible for the spatial exclusion of HMR-1, however remain elusive. Here, we show that HMR-1 is actively prevented from entering the cytokinetic furrow zone during early embryonic divisions in C. elegans. The compact alignment of unbranched F-actin filaments polymerized by the formin/CYK-1 restricts HMR-1 from entering the ingressing furrow. This corralling phenomenon depends on the physical association between HMR-1 and F-actin mediated via the {beta}- and - catenins, HMP-2 and HMP-1, respectively. Our findings reveal a previously unknown reciprocal regulatory relationship between cell adhesion and cell division machineries, ensuring the precise orchestration of the cytokinesis during embryonic development.

cell biology↗

bioRxiv2023

Characterization of genetic and molecular tools for studying the endogenous expression of Lactate dehydrogenase in Drosophila melanogaster

Drosophila melanogaster larval development relies on a specialized metabolic state that utilizes carbohydrates and other dietary nutrients to promote rapid growth. One unique feature of the larval metabolic program is that Lactate Dehydrogenase (Ldh) activity is highly elevated during this growth phase when compared to other stages of the fly life cycle, indicating that Ldh serves a key role in promoting juvenile development. Previous studies of larval Ldh activity have largely focused on the function of this enzyme at the whole animal level, however, Ldh expression varies significantly among larval tissues, raising the question of how this enzyme promotes tissue-specific growth programs. Here we characterize two transgene reporters and an antibody that can be used to study Ldh expression in vivo. We find that all three tools produce similar Ldh expression patterns. Moreover, these reagents demonstrate that the larval Ldh expression pattern is complex, suggesting the purpose of this enzyme varies across cell types. Overall, our studies validate a series of genetic and molecular reagents that can be used to study glycolytic metabolism in the fly.

developmental biology↗

bioRxiv2023

Bird communities in a selectively logged tropical montane forest are dominated by small, low-elevation species

Tropical montane forests are critical centres of terrestrial biodiversity and endemism, and face a range of threats, including selective logging and climate change. However, few studies have explored the joint influence of these threats, particularly in tropical mountains, despite how crucial it is to understand the cumulative impact of forest loss and climate change on biodiversity. We used mist-netting and bird ringing data from a long-term (10-year) community and population monitoring program to examine how the composition of the mid-elevation Eastern Himalayan understorey bird community changed in the mid-elevation primary and logged forest. Because logged forest is warmer than primary forest, we hypothesised that the bird community would shift towards lower elevation species, with a faster transition in logged forest. Further, because logged forest has lower arthropod abundance, we hypothesised that the primary forest community would have larger species than the logged forest community. Our study shows that the bird community in the logged forest shifted towards lower-elevation species than in the primary forest (although this was not statistically significant). Moreover, we found that smaller species were better able to colonise warmer logged forest, whereas larger species reached higher densities in primary forest. These trends are likely to be driven by climate change causing upslope range shifts and logged forest selecting for species that are likely to tolerate the consequently altered abiotic (higher temperatures) and biotic (lower resources) environment. These findings have significant implications for understanding the impacts of forest loss and climate change on biodiversity, particularly in tropical montane forests.

ecology↗

bioRxiv2022

The effect of selective logging on microclimates, arthropod abundance and the foraging behaviour of Eastern Himalayan birds

1. Selective logging--the practice of removing a subset of commercially important trees from a forest--is a globally pervasive form of forest degradation. Selective logging alters both the structure and function of forests and the composition of ecological communities. 2. Tropical insectivorous birds are highly vulnerable to microhabitat alterations in logged forest. Such altered microhabitats might affect the foraging of forest birds by altering (a) resource availability, and (b) foraging behaviour. 3. We investigated the effect of selective logging on microclimates, prey availability, foraging behaviour and the foraging success of eastern Himalayan birds in the breeding season. 4. Selective logging alters temperature-humidity microclimates and the composition of arthropod communities, both of which are likely to then collectively alter foraging behaviour by birds. We show that birds spent a lower proportion of their time foraging in primary compared with logged forest. Further, selective logging interacts with species traits such as body mass, preferred foraging stratum (understorey, midstorey or canopy) and foraging manoeuvre to influence foraging success. Gleaners generally foraged more successfully in primary forest and salliers in logged forest, although these patterns were modified by body mass and foraging stratum. 5. Synthesis and applications: Our study shows how altered microclimates in anthropogenically modified habitats can influence resource availability and have downstream impacts on the behaviour of species at higher trophic levels.

ecology↗

bioRxiv2022

The Drosophila melanogaster enzyme glycerol-3-phosphate dehydrogenase 1 is required for oogenesis, embryonic development, and amino acid homeostasis

As the fruit fly, Drosophila melanogaster, progresses from one life stage to the next, many of the enzymes that compose intermediary metabolism undergo substantial changes in both expression and activity. These predictable shifts in metabolic flux allow the fly meet stage-specific requirements for energy production and biosynthesis. In this regard, the enzyme Glyerol-3-phosphate dehydrogenase (GPDH1) has been the focus of biochemical genetics studies for several decades, and as a result, is one of the most well characterized Drosophila enzymes. Among the findings of these earlier studies is that GPDH1 acts throughout the fly lifecycle to promote mitochondrial energy production and triglyceride accumulation while also serving a key role in maintaining redox balance. Here we expand upon the known roles of GPDH1 during fly development by examining how depletion of both the maternal and zygotic pools of this enzyme influences development, metabolism, and viability. Our findings not only confirm previous observations that Gpdh1 mutants exhibit defects in larval development, lifespan, and fat storage but also reveal that GPDH1 serves essential roles in oogenesis and embryogenesis. Moreover, metabolomics analysis reveals that a Gpdh1 mutant stock maintained in a homozygous state exhibits larval metabolic defects that significantly differ from those observed in the F1 mutant generation. Overall, our findings highlight unappreciated roles for GPDH1 in early development and uncover previously undescribed metabolic adaptations that could allow flies to survive loss of this key enzyme.

developmental biology↗

bioRxiv2021

Seeing the unseen: A trifoliate (MYB117) mutant allele fortifies folate and carotenoids in tomato fruits

Micronutrient deficiency also termed hidden hunger affects a large segment of the human population, particularly in developing and underdeveloped nations. Tomato the second most consumed vegetable crop in the world after potato can serve as a sustainable source to alleviate micronutrient deficiency. In tomato, the mutations in the R2R3-MYB117 transcription factor elicit trifoliate leaves and initiate axillary meristems; however, its effect on fruit metabolome remains unexplored. The fruits of a new trifoliate (tf) allele (tf-5) were firmer, had higher {degrees}Brix, folate, and carotenoids. The transcriptome, proteome, and metabolome profiling of tf-5 reflected a broad-spectrum change in homeostasis. The tf-5 allele enhanced the fruit firmness by suppressing cell wall softening-related proteins. The tf-5 fruit displayed a substantial increase in aminome, particularly {gamma}-aminobutyric acid, with a parallel reduction in aminoacyl t-RNA synthases. The increased lipoxygenases proteins and transcripts seemingly elevated jasmonic acid. In addition, increased abscisic acid hydrolases transcripts coupled with reduced precursor supply lowered abscisic acid. The upregulation of carotenoids was mediated by modulation of methylerythreitol and plastoquinone pathways along with an increase in carotenoids isomerization proteins. The upregulation of folate in tf-5 was connoted by the increase in precursor p-aminobenzoic acid and transcripts of several folate biosynthesis pathway genes. The reduction in pterin-6-carboxylate and {gamma}-glutamyl hydrolase activity indicated that the diminished folate degradation also enriched folate levels. Our study delineates that introgression of the tf-5 can be used for the {gamma}-aminobutyric acid, carotenoids, and folate fortification of tomato. One-sentence summaryA tomato trifoliate allele encoding a truncated MYB117 transcription factor alters cellular homeostasis and fortifies {gamma}-aminobutyric acid, folate, and carotenoids in tomato fruits.

plant biology↗

bioRxiv2020

Mutations in Tomato 1-Aminocyclopropane Carboxylic Acid Synthase2 Uncover Its Role in Development beside System II Responses

The role of ethylene in plant development is mostly inferred from its exogenous application. The usage of the mutants affecting ethylene biosynthesis proffers a better alternative to decipher its role. In tomato, 1-aminocyclopropane carboxylic acid synthase2 (ACS2) is a key enzyme regulating ripening-specific ethylene biosynthesis. We characterized two contrasting acs2 mutants; acs2-1 overproduces ethylene, has higher ACS activity, and increased protein levels, while acs2-2 is an ethylene under-producer, displays lower ACS activity, and protein levels than wild type. Consistent with high/low ethylene emission, the mutants show opposite phenotypes, physiological responses, and metabolomic profiles than the wild type. The acs2-1 showed early seed germination, faster leaf senescence, and accelerated fruit ripening. Conversely, acs2-2 had delayed seed germination, slower leaf senescence, and prolonged fruit ripening. The phytohormone profiles of mutants were mostly opposite in the leaves and fruits. The faster/slower senescence of acs2-1/acs2-2 leaves correlated with the endogenous ethylene/zeatin ratio. The genetic analysis showed that the metabolite profiles of respective mutants co-segregated with the homozygous mutant progeny. Our results uncover that besides ripening, ACS2 participates in vegetative and reproductive development of tomato. The distinct influence of ethylene on phytohormone profiles indicates intertwining of ethylene action with other phytohormones in regulating plant development.

plant biology↗

bioRxiv2019

Induced pluripotent stem cell-derived primary proprioceptive neurons as Friedreich ataxia cell model

Human induced pluripotent stem cells (iPSCs) are used to generate models of human diseases that recapitulate the pathogenic process as it occurs in affected cells. Many differentiated cell types can currently be obtained from iPSCs, but no validated protocol is yet available to specifically generate primary proprioceptive neurons. Proprioceptors are affected in a number of genetic and acquired diseases, including Friedreich ataxia (FRDA).\n\nFRDA is a recessive neurodegenerative and systemic disease due to epigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at the FXN locus. The most characteristic early neuropathologic finding in FRDA is the loss of large primary proprioceptive neurons in the dorsal root ganglia (DRGs), with associated loss of large myelinated fibers in the dorsal roots and in the posterior columns of the spinal cord. Both a developmental deficit and progressive neurodegeneration are thought to underlie the loss of proprioceptors in FRDA, though the relative contribution of these two components is unclear. The basis of the high specific vulnerability of proprioceptors in FRDA is also unknown. In order to address these open questions about FRDA pathogenesis and at the same time develop a cell model that can be applied to other conditions primarily affecting proprioceptors, we set up a protocol to differentiate iPSCs into primary proprioceptive neurons. We modified the dual-SMAD inhibition/WNT activation protocol, previously used to generate nociceptor-enriched cultures of primary sensory neurons from iPSCs, to favor instead the generation of proprioceptors. We succeeded in substantially enriching iPSC-derived primary sensory neuron cultures in proprioceptors, largely exceeding the proportion normally represented by these cells in dorsal root ganglia. We also showed that almost pure populations of proprioceptors can be purified from these cultures by fluorescence-activated cell sorting. Finally, we demonstrated that iPSCs from a FRDA patient can generate normal appearing proprioceptors but have subtle differentiation deficits and more limited survival.

neuroscience↗

bioRxiv2017

Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor.

Epigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at the FXN locus is the key pathogenic event in Friedreich ataxia (FRDA), a recessive neurodegenerative and systemic disease. FXN is involved in iron-sulfur (Fe-S) cluster biogenesis in mitochondria, its deficiency causes multiple Fe-S protein deficiencies, mitochondrial dysfunction and oxidative stress. Primary sensory neurons (PSNs) in the dorsal root ganglia (DRGs) are the most vulnerable cells in FRDA, whose abnormal development and degeneration leads to the onset and early progression of ataxia. We generated PSNs from induced pluripotent stem cells (iPSCs) from FRDA patients and showed that they recapitulate the key pathogenic events in FRDA, including low FXN levels, loss of Fe-S proteins and impaired antioxidant responses. We also showed that FXN deficiency in these cells may be partially corrected by a pimelic benzamide histone deacetylase inhibitor, a class of potential therapeutics for FRDA. We generated and validated a cellular model of the most vulnerable neurons in FRDA, which can be used for further studies on pathogenesis and treatment approaches.

neuroscience↗