Suman Rimal

All Publications

• Reverse electron transfer is activated during aging and contributes to aging and age-related disease. EMBO reports Rimal, S., Tantray, I., Li, Y., Pal Khaket, T., Li, Y., Bhurtel, S., Li, W., Zeng, C., Lu, B. 2023: e55548

  Abstract

  Mechanisms underlying the depletion of NAD+ and accumulation of reactive oxygen species (ROS) in aging and age-related disorders remain poorly defined. We show that reverse electron transfer (RET) at mitochondrial complex I, which causes increased ROS production and NAD+ to NADH conversion and thus lowered NAD+ /NADH ratio, is active during aging. Genetic or pharmacological inhibition of RET decreases ROS production and increases NAD+ /NADH ratio, extending the lifespan of normal flies. The lifespan-extending effect of RET inhibition is dependent on NAD+ -dependent Sirtuin, highlighting the importance of NAD+ /NADH rebalance, and on longevity-associated Foxo and autophagy pathways. RET and RET-induced ROS and NAD+ /NADH ratio changes are prominent in human induced pluripotent stem cell (iPSC) model and fly models of Alzheimer's disease (AD). Genetic or pharmacological inhibition of RET prevents the accumulation of faulty translation products resulting from inadequate ribosome-mediated quality control, rescues relevant disease phenotypes, and extends the lifespan of Drosophila and mouse AD models. Deregulated RET is therefore a conserved feature of aging, and inhibition of RET may open new therapeutic opportunities in the context of aging and age-related diseases including AD.

  View details for DOI 10.15252/embr.202255548

  View details for PubMedID 36794623

• The mTORC2/AKT/VCP axis is associated with quality control of the stalled translation of poly(GR) dipeptide repeats in C9-ALS/FTD. The Journal of biological chemistry Li, Y., Geng, J., Rimal, S., Wang, H., Liu, X., Lu, B., Li, S. 2023: 102995

  Abstract

  Expansion of G4C2 hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis with frontotemporal dementia (C9-ALS/FTD). Dipeptide repeats (DPRs) generated by unconventional translation, especially the R-containing poly(GR), have been implicated in C9-ALS/FTD pathogenesis. Mutations in other genes, including TAR DNA-binding protein 43 KD (TDP-43), fused in sarcoma (FUS), and valosin-containing protein (VCP), have also been linked to ALS/FTD, and upregulation of amyloid precursor protein (APP) is observed at the early stage of ALS and FTD. Fundamental questions remain as to the relationships between these ALS/FTD genes and whether they converge on similar cellular pathways. Here, using biochemical, cell biological, and genetic analyses in Drosophila disease models, patient-derived fibroblasts, and mammalian cell culture, we show that mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling is activated by APP, TDP-43, and FUS, and that mTORC2/AKT and its downstream target VCP mediate the effect of APP, TDP-43, and FUS on the quality control of C9-ALS/FTD-associated poly(GR) translation. We also find that poly(GR) expression results in reduction of global translation, and that the co-expression of APP, TDP-43, and FUS results in further reduction of global translation, presumably through the GCN2/eIF2alpha integrated stress response pathway. Together, our results implicate mTORC2/AKT signaling and GCN2/eIF2alpha integrated stress response as common signaling pathways underlying ALS/FTD pathogenesis.

  View details for DOI 10.1016/j.jbc.2023.102995

  View details for PubMedID 36764521

• Prevention of ribosome collision-induced neuromuscular degeneration by SARS CoV-2-encoded Nsp1. Proceedings of the National Academy of Sciences of the United States of America Wang, X., Rimal, S., Tantray, I., Geng, J., Bhurtel, S., Khaket, T. P., Li, W., Han, Z., Lu, B. 2022; 119 (42): e2202322119

  Abstract

  An overarching goal of aging and age-related neurodegenerative disease research is to discover effective therapeutic strategies applicable to a broad spectrum of neurodegenerative diseases. Little is known about the extent to which targetable pathogenic mechanisms are shared among these seemingly diverse diseases. Translational control is critical for maintaining proteostasis during aging. Gaining control of the translation machinery is also crucial in the battle between viruses and their hosts. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic. Here, we show that overexpression of SARS-CoV-2-encoded nonstructural protein 1 (Nsp1) robustly rescued neuromuscular degeneration and behavioral phenotypes in Drosophila models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These diseases share a common mechanism: the accumulation of aberrant protein species due to the stalling and collision of translating ribosomes, leading to proteostasis failure. Our genetic and biochemical analyses revealed that Nsp1 acted in a multipronged manner to resolve collided ribosomes, abort stalled translation, and remove faulty translation products causative of disease in these models, at least in part through the ribosome recycling factor ABCE1, ribosome-associated quality-control factors, autophagy, and AKT signaling. Nsp1 exhibited exquisite specificity in its action, as it did not modify other neurodegenerative conditions not known to be associated with ribosome stalling. These findings uncover a previously unrecognized mechanism of Nsp1 in manipulating host translation, which can be leveraged for combating age-related neurodegenerative diseases that are affecting millions of people worldwide and currently without effective treatment.

  View details for DOI 10.1073/pnas.2202322119

  View details for PubMedID 36170200

• Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells. Developmental cell Ojha, R., Tantray, I., Rimal, S., Mitra, S., Cheshier, S., Lu, B. 1800; 57 (2): 260

  Abstract

  Metabolic flexibility is a hallmark of many cancers where mitochondrial respiration is critically involved, but the molecular underpinning of mitochondrial control of cancer metabolic reprogramming is poorly understood. Here, we show that reverse electron transfer (RET) through respiratory chain complex I (RC-I) is particularly active in brain cancer stem cells (CSCs). Although RET generates ROS, NAD+/NADH ratio turns out to be key in mediating RET effect on CSC proliferation, in part through the NAD+-dependent Sirtuin. Mechanistically, Notch acts in an unconventional manner to regulate RET by interacting with specific RC-I proteins containing electron-transporting Fe-S clusters and NAD(H)-binding sites. Genetic and pharmacological interference of Notch-mediated RET inhibited CSC growth in Drosophila brain tumor and mouse glioblastoma multiforme (GBM) models. Our results identify Notch as a regulator of RET and RET-induced NAD+/NADH balance, a critical mechanism of metabolic reprogramming and a metabolic vulnerability of cancer that may be exploited for therapeutic purposes.

  View details for DOI 10.1016/j.devcel.2021.12.020

  View details for PubMedID 35077680

• Inefficient quality control of ribosome stalling during APP synthesis generates CAT-tailed species that precipitate hallmarks of Alzheimer's disease. Acta neuropathologica communications Rimal, S., Li, Y., Vartak, R., Geng, J., Tantray, I., Li, S., Huh, S., Vogel, H., Glabe, C., Grinberg, L. T., Spina, S., Seeley, W. W., Guo, S., Lu, B. 2021; 9 (1): 169

  Abstract

  Amyloid precursor protein (APP) metabolism is central to Alzheimer's disease (AD) pathogenesis, but the key etiological driver remains elusive. Recent failures of clinical trials targeting amyloid-beta (Abeta) peptides, the proteolytic fragments of amyloid precursor protein (APP) that are the main component of amyloid plaques, suggest that the proteostasis-disrupting, key pathogenic species remain to be identified. Previous studies suggest that APP C-terminal fragment (APP.C99) can cause disease in an Abeta-independent manner. The mechanism of APP.C99 pathogenesis is incompletely understood. We used Drosophila models expressing APP.C99 with the native ER-targeting signal of human APP, expressingfull-length human APP only, or co-expressing full-length human APP and beta-secretase (BACE), to investigate mechanisms of APP.C99 pathogenesis. Key findings are validated in mammalian cell culture models, mouse 5xFAD model, and postmortem AD patient brain materials. We find that ribosomes stall at the ER membrane during co-translational translocation of APP.C99, activating ribosome-associated quality control (RQC) to resolve ribosome collision andstalled translation. StalledAPP.C99 species with C-terminal extensions (CAT-tails) resulting from inadequate RQC are prone to aggregation, causing endolysosomal and autophagy defects and seeding the aggregation of amyloid beta peptides, the main component of amyloid plaques. Genetically removing stalled and CAT-tailed APP.C99 rescued proteostasis failure, endolysosomal/autophagy dysfunction, neuromuscular degeneration, and cognitive deficits in AD models. Our findingofRQC factor deposition at the core of amyloid plaques from AD brains further supports the central role of defective RQC of ribosome collision andstalled translation in AD pathogenesis. These findings demonstrate that amyloid plaque formation is the consequence and manifestation of a deeper level proteostasis failure caused by inadequate RQC of translationalstallingand the resultantaberrantly modified APP.C99 species, previously unrecognized etiological drivers of ADandnewly discovered therapeutic targets.

  View details for DOI 10.1186/s40478-021-01268-6

  View details for PubMedID 34663454

• Cucurbitacin B Activates Bitter-Sensing Gustatory Receptor Neurons via Gustatory Receptor 33a in Drosophila melanogaster. Molecules and cells Rimal, S., Sang, J., Dhakal, S., Lee, Y. 2020; 43 (6): 530-538

  Abstract

  The Gustatory system enables animals to detect toxic bitter chemicals, which is critical for insects to survive food induced toxicity. Cucurbitacin is widely present in plants such as cucumber and gourds that acts as an anti-herbivore chemical and an insecticide. Cucurbitacin has a harmful effect on insect larvae as well. Although various beneficial effects of cucurbitacin such as alleviating hyperglycemia have also been documented, it is not clear what kinds of molecular sensors are required to detect cucurbitacin in nature. Cucurbitacin B, a major bitter component of bitter melon, was applied to induce action potentials from sensilla of a mouth part of the fly, labellum. Here we identify that only Gr33a is required for activating bitter-sensing gustatory receptor neurons by cucurbitacin B among available 26 Grs, 23 Irs, 11 Trp mutants, and 26 Gr-RNAi lines. We further investigated the difference between control and Gr33a mutant by analyzing binary food choice assay. We also measured toxic effect of Cucurbitacin B over 0.01 mM range. Our findings uncover the molecular sensor of cucurbitacin B in Drosophila melanogaster. We propose that the discarded shell of Cucurbitaceae can be developed to make a new insecticide.

  View details for DOI 10.14348/molcells.2020.0019

  View details for PubMedID 32451368

• Molecular sensor of nicotine in taste of Drosophila melanogaster INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY Rimal, S., Lee, Y. 2019; 111: 103178

  Abstract

  Nicotine is an alkaloid and potent parasympathomimetic stimulant found in the leaves of many plants including Nicotiana tabacum, which functions as an anti-herbivore chemical and an insecticide. Chemoreceptors embedded in the gustatory receptor neurons (GRNs) enable animals to judge the quality of bitter compounds and respond to them. Various taste receptors such as gustatory receptors (GRs), ionotropic receptors (IRs), transient receptor potential channels (TRPs), and pickpocket channels (PPKs) have been shown to have important roles in taste sensation. However, the mechanism underlying nicotine taste sensation has not been resolved in the insect model. Here we identify molecular receptors to detect the taste of nicotine and provide electrophysiological and behavioral evidence that gustatory receptors are required for avoiding nicotine-laced foods. Our results demonstrate that gustatory receptors are reasonable targets to develop new pesticides that maximize the insecticidal effects of nicotine.

  View details for DOI 10.1016/j.ibmb.2019.103178

  View details for Web of Science ID 000478706500007

  View details for PubMedID 31226410

• Mechanism of Acetic Acid Gustatory Repulsion in Drosophila CELL REPORTS Rimal, S., Sang, J., Poudel, S., Thakur, D., Montell, C., Lee, Y. 2019; 26 (6): 1432-+

  Abstract

  The decision to consume or reject a food based on the degree of acidity is critical for animal survival. However, the gustatory receptors that detect sour compounds and influence feeding behavior have been elusive. Here, using the fly, Drosophila melanogaster, we reveal that a member of the ionotropic receptor family, IR7a, is essential for rejecting foods laced with high levels of acetic acid. IR7a is dispensable for repulsion of other acidic compounds, indicating that the gustatory sensation of acids occurs through a repertoire rather than a single receptor. The fly's main taste organ, the labellum, is decorated with bristles that house dendrites of gustatory receptor neurons (GRNs). IR7a is expressed in a subset of bitter GRNs rather than GRNs dedicated to sour taste. Our findings indicate that flies taste acids through a repertoire of receptors, enabling them to discriminate foods on the basis of acid composition rather than just pH.

  View details for DOI 10.1016/j.celrep.2019.01.042

  View details for Web of Science ID 000457709200007

  View details for PubMedID 30726729

  View details for PubMedCentralID PMC6490183

• Gustatory receptor 28b is necessary for avoiding saponin in Drosophila melanogaster EMBO REPORTS Sang, J., Rimal, S., Lee, Y. 2019; 20 (2)

  Abstract

  Saponins function as a natural self-defense mechanism for plants to deter various insects due to their unpleasant taste and their toxicity. Here, we provide evidence that saponin from Quillaja saponaria functions as an antifeedant as well as an insecticide to ward off insects in both the larval and the adult stages. Using a behavioral screen of 26 mutant fly lines, we show that the Gr28b gene cluster plays a role in saponin avoidance in the labellum. The Gr28b mutant does not avoid saponin and exhibits increased lethality when fed saponin-mixed food. Tissue-specific rescue experiments with five different Gr28b isoforms revealed that only the Gr28b.c isoform is required for saponin sensation. We propose that in contrast to sensing many other bitter compounds, saponin sensing does not require the function of core taste receptors, such as GR32a, GR33a, and GR66a. Our results reveal a novel role for GR28b in taste. In addition, the ability of saponin to act as insecticides as well as antifeedants suggests its potential application in controlling insect pests.

  View details for DOI 10.15252/embr.201847328

  View details for Web of Science ID 000459026000012

  View details for PubMedID 30622216

  View details for PubMedCentralID PMC6362386

• The multidimensional ionotropic receptors of Drosophila melanogaster INSECT MOLECULAR BIOLOGY Rimal, S., Lee, Y. 2018; 27 (1): 1–7

  Abstract

  Ionotropic receptors (IRs), which form ion channels, can be categorized into conserved 'antennal IRs', which define the first olfactory receptor family of insects, and species-specific 'divergent IRs', which are expressed in gustatory receptor neurones. These receptors are located primarily in cell bodies and dendrites, and are highly enriched in the tips of the dendritic terminals that convey sensory information to higher brain centres. Antennal IRs play important roles in odour and thermosensation, whereas divergent IRs are involved in other important biological processes such as taste sensation. Some IRs are known to play specific biological roles in the perception of various molecules; however, many of their functions have not yet been defined. Although progress has been made in this field, many functions and mechanisms of these receptors remain unknown. In this review, we provide a comprehensive summary of the current state of knowledge in this field.

  View details for DOI 10.1111/imb.12347

  View details for Web of Science ID 000419247300001

  View details for PubMedID 28857341