Publication profile

Saurav Ghimire iD

Scientific staff

Publications

Generated from ORCID where available; fallback PubMed/NCBI records require manual review. Current Albert Lab members are underlined in the author lists.

2026

2026 · Publication

The autophagy core protein Atg18 regulates exosome release and rescues pathogenic dysfunction associated to Parkinson Sac domain mutation in Synaptojanin

Irene Sanchez-Mirasierra, Sergio Hernández-Díaz, Liam Barry-Carroll, Aida Arjona Martí, Saurav Ghimire, Jean-Christophe Delpech, Sandra-Fausia Soukup

ABSTRACT Macroautophagy, a catabolic process conserved across evolution, participates in fundamental aspects of synaptic function and neuronal survival. Exosomes are extracellular vesicles that mediate cell communication, including emerging roles mediating brain intercellular signaling, synaptic function and neuronal survival. Indeed, both autophagy and exosome release interact with each other, but this interplay is poorly characterized at the neuronal synapse, especially in the context of neurodegenerative diseases. Here, we report that at the presynaptic compartment the autophagy protein Atg18a/WIPI2 regulates exosome release at the level of the multivesicular body. The Parkinson disease mutation R258Q in the protein Synaptojanin inhibits synaptic autophagy, and causes locomotion deficits, seizures and neurodegeneration. We found that this mutation also reduces exosome release and that the dopaminergic overexpression of Atg18a in Synaptojanin mutant animals restores exosome release, locomotion and dopaminergic survival without restoring synaptic autophagy. Our data reports a novel function of Atg18a in the regulation of exosome release and spotlights the role of exosome release in the pathogenesis of Parkinson disease.

2023

2023 · bioRxiv

Synaptogyrin regulates neuronal activity-induced autophagy to degrade synaptic vesicle components and pathological Tau

Sergio Hernandez-Diaz, Pilar Martinez-Olondo, Irene Sanchez-Mirasierra, Carla Montecinos, Saurav Ghimire, James D. Sutherland, Rosa Barrio, Sandra-Fausia Soukup

Abstract Synapses are specialized neuronal compartments essential for brain communication. Neuronal communication mostly relies on the adequate supply and renovation of synaptic vesicles that fuse with the plasma membrane and release neurotransmitters in response to action potentials. Autophagy is an evolutionary conserved cellular mechanism essential for homeostasis that can be locally regulated in the neuronal synapse. However, the precise mechanisms controlling synaptic autophagy, especially during neuronal communication and pathological scenarios, remain elusive. Here, we report that neuronal activity and amino-acid deprivation regulate synaptic autophagy via distinct molecular mechanisms. We show that Synaptogyrin, a highly abundant presynaptic protein found in synaptic vesicles, is a novel negative regulator of synaptic autophagy in response to neuronal activity without affecting autophagy induction via amino-acid deprivation. We demonstrate that loss of Synaptogyrin modifies the localization of the autophagy protein Atg9 and boosts autophagosome formation at the synapse. Furthermore, activation of synaptic autophagy by loss of Synaptogyrin, but not by amino-acid deprivation, leads to the degradation of synaptic vesicle components via autophagy. Reducing the levels of Synaptogyrin results in the degradation of synaptic Tau via autophagy and restores autophagy dysfunction observed in a Drosophila Tau model of Frontotemporal Dementia (FTD). Our data provide novel and valuable information to understand how autophagy is regulated at the synapse in response to neuronal activity and how this process participates in neuronal (dys)function.

2022

2022 · Frontiers in Cell and Developmental Biology

Targeting Macroautophagy as a Therapeutic Opportunity to Treat Parkinson’s Disease

Irene Sanchez-Mirasierra, Saurav Ghimire, Sergio Hernandez-Diaz, Sandra-Fausia Soukup

Macroautophagy, an evolutionary conserved catabolic process in the eukaryotic cell, regulates cellular homeostasis and plays a decisive role in self-engulfing proteins, protein aggregates, dysfunctional or damaged organelles, and invading pathogens. Growing evidence from in vivo and in vitro models shows that autophagy dysfunction plays decisive role in the pathogenesis of various neurodegenerative diseases, including Parkinson’s disease (PD). PD is an incurable and second most common neurodegenerative disease characterised by neurological and motor dysfunction accompanied of non-motor symptoms that can also reduce the life quality of patients. Despite the investment in research, the aetiology of the disease is still unknown and the therapies available are aimed mostly at ameliorating motor symptoms. Hence, therapeutics regulating the autophagy pathway might play an important role controlling the disease progression, reducing neuronal loss and even ameliorating non-motor symptoms. In this review, we highlight potential therapeutic opportunities involved in different targeting options like an initiation of autophagy, Leucine-rich repeat kinase 2 (LRRK2) inhibition, mitophagy, lysosomes, lipid metabolism, immune system, gene expression, biomarkers, and also non-pharmacological interventions. Thus, strategies to identify therapeutics targeting the pathways modulating autophagy might hold a future for therapy development against PD.

2022 · Neurobiology of Disease

Endophilin-B regulates autophagy during synapse development and neurodegeneration

Sergio Hernandez-Diaz, Saurav Ghimire, Irene Sanchez-Mirasierra, Carla Montecinos-Oliva, Jef Swerts, Sabine Kuenen, Patrik Verstreken, Sandra-Fausia Soukup

This publication investigates Endophilin-B regulates autophagy during synapse development and neurodegeneration.

2022 · Autophagy in Health and Disease

Altered autophagy on the path to Parkinson’s disease

Irene Sanchez-Mirasierra, Sergio Hernandez-Diaz, Saurav Ghimire, Patrick Main, Sandra-Fausia Soukup

This publication investigates Altered autophagy on the path to Parkinson’s disease.

2021

2021 · Journal of Agricultural and Food Chemistry

Moringa oleifera: A Tree of Life as a Promising Medicinal Plant for Neurodegenerative Diseases

Saurav Ghimire, Lalita Subedi, Namrata Acharya, Bhakta Prasad Gaire

This publication investigates Moringa oleifera: A Tree of Life as a Promising Medicinal Plant for Neurodegenerative Diseases.

2021 · Frontiers in Cell and Developmental Biology

Macros to Quantify Exosome Release and Autophagy at the Neuromuscular Junction of Drosophila Melanogaster

Irene Sanchez-Mirasierra, Sergio Hernandez-Diaz, Saurav Ghimire, Carla Montecinos-Oliva, Sandra-Fausia Soukup

Automatic quantification of image parameters is a powerful and necessary tool to explore and analyze crucial cell biological processes. This article describes two ImageJ/Fiji automated macros to approach the analysis of synaptic autophagy and exosome release from 2D confocal images. Emerging studies point out that exosome biogenesis and autophagy share molecular and organelle components. Indeed, the crosstalk between these two processes may be relevant for brain physiology, neuronal development, and the onset/progression of neurodegenerative disorders. In this context, we describe here the macros “Autophagoquant” and “Exoquant” to assess the quantification of autophagosomes and exosomes at the neuronal presynapse of the Neuromuscular Junction (NMJ) in Drosophila melanogaster using confocal microscopy images. The Drosophila NMJ is a valuable model for the study of synapse biology, autophagy, and exosome release. By use of Autophagoquant and Exoquant, researchers can have an unbiased, standardized, and rapid tool to analyze autophagy and exosomal release in Drosophila NMJ. Code available at: https://github.com/IreneSaMi/Exoquant-Autophagoquant

2020

2020 · Proceedings of the National Academy of Sciences

Specialized stellate cells offer a privileged route for rapid water flux in Drosophila renal tubule

Pablo Cabrero, Selim Terhzaz, Anthony J. Dornan, Saurav Ghimire, Heather L. Holmes, Daniel R. Turin, Michael F. Romero, Shireen A. Davies, Julian A. T. Dow

Significance The tiny insect renal (Malpighian) tubule can transport fluid at unparalleled speed, suggesting unique specializations. Here we show that strategic allocation of major intrinsic proteins (MIPs) to specific cells within the tubule allows the separation of metabolically intense active cation transport from passive chloride and water conductance. This specialized renal architecture is general to at least many higher insects, providing a clue to the unique success of the class Insecta in colonizing an extraordinary range of ecological niches.

2019

2019 · bioRxiv

When two cells are better than one: specialized stellate cells provide a privileged route for uniquely rapid water flux in Drosophila renal tubule

Pablo Cabrero, Selim Terhzaz, Anthony J. Dornan, Saurav Ghimire, Heather L. Holmes, Daniel R. Turin, Michael F. Romero, Shireen A. Davies, Julian A. T. Dow

Abstract Insects are highly successful, in part through an excellent ability to osmoregulate. The renal (Malpighian) tubules can secrete fluid faster on a per-cell basis than any other epithelium, but the route for these remarkable water fluxes has not been established. In Drosophila melanogaster , we show that 4 members of the Major Intrinsic Protein family are expressed at very high level in the fly renal tissue; the aquaporins Drip and Prip, and the aquaglyceroporins Eglp2 and Eglp4. As predicted from their structure and by their transport function by expressing these proteins in Xenopus oocytes, Drip, Prip and Eglp2 show significant and specific water permeability, whereas Eglp2 and Eglp4 show very high permeability to glycerol and urea. Knockdowns of any of these genes impacts tubule performance resulting in impaired hormone-induced fluid secretion. The Drosophila tubule has two main secretory cell types: active cation-transporting principal cells with the aquaglyceroporins localize to opposite plasma membranes and small stellate cells, the site of the chloride shunt conductance, with these aquaporins localising to opposite plasma membranes. This suggests a model in which cations are pumped by the principal cells, causing chloride to follow through the stellate cells in order to balance the charge. As a consequence, osmotically obliged water follows through the stellate cells. Consistent with this model, fluorescently labelled dextran, an in vivo marker of membrane water permeability, is trapped in the basal infoldings of the stellate cells after kinin diuretic peptide stimulation, confirming that these cells provide the major route for transepithelial water flux. The spatial segregation of these components of epithelial water transport may help to explain the unique success of the higher insects. Significance statement The tiny insect renal (Malpighian) tubule can transport fluid at unparalleled speed, suggesting unique specialisations. Here we show that strategic allocation of Major Intrinsic Proteins (MIPs) to specific cells within the polarized tubule allow the separation of metabolically intense active cation transport from chloride and water conductance. This body plan is general to at least many higher insects, providing a clue to the unique success of the class Insecta.

2019 · American Journal of Physiology-Renal Physiology

Targeted renal knockdown of Na+/H+ exchanger regulatory factor Sip1 produces uric acid nephrolithiasis in Drosophila

Saurav Ghimire, Selim Terhzaz, Pablo Cabrero, Michael F. Romero, Shireen A. Davies, Julian A. T. Dow

Nephrolithiasis is one of the most common kidney diseases, with poorly understood pathophysiology, but experimental study has been hindered by lack of experimentally tractable models. Drosophila melanogaster is a useful model organism for renal diseases because of genetic and functional similarities of Malpighian (renal) tubules with the human kidney. Here, we demonstrated function of the sex-determining region Y protein-interacting protein-1 ( Sip1) gene, an ortholog of human Na + /H + exchanger regulatory factor ( NHERF1), in Drosophila Malpighian tubules and its impact on nephrolithiasis. Abundant birefringent calculi were observed in Sip1 mutant flies, and the phenotype was also observed in renal stellate cell-specific RNA interference Sip1 knockdown in otherwise normal flies, confirming a renal etiology. This phenotype was abolished in rosy mutant flies (which model human xanthinuria) and by the xanthine oxidase inhibitor allopurinol, suggesting that the calculi were of uric acid. This was confirmed by direct biochemical assay for urate. Stones rapidly dissolved when the tubule was bathed in alkaline media, suggesting that Sip1 knockdown was acidifying the tubule. SIP1 was shown to collocate with Na + /H + exchanger isoform 2 (NHE2) and with moesin in stellate cells. Knockdown of NHE2 specifically to the stellate cells also increased renal uric acid stone formation, and so a model was developed in which SIP1 normally regulates NHE2 activity and luminal pH, ultimately leading to uric acid stone formation. Drosophila renal tubules may thus offer a useful model for urate nephrolithiasis.

2019 · Methods in Molecular Biology

Epithelial function in the Drosophila Malpighian Tubule: An in vivo renal model

Shireen-A. Davies, Pablo Cabrero, Richard Marley, Guillermo Martinez Corrales, Saurav Ghimire, Anthony J. Dornan, Julian A. T. Dow

This publication investigates Epithelial function in the Drosophila Malpighian Tubule: An in vivo renal model.

2018

2018 · Rejuvenation Research

Ilex paraguariensis extends lifespan and increases an ability to resist environmental stresses in drosophila

Prakshit Niraula, Saurav Ghimire, Hanna Lee, Man Su Kim

Aging is a complex process resulting in (1) a decline in body functions and capacity to withstand environmental stress and (2) an increased susceptibility to diseases including, but not limited to, cardiovascular disorders, diabetes, cancer, and dementia. Among a number of herbal products used to alleviate symptoms associated with aging is Ilex paraguariensis (IP). This product has been reported to have anticancer, anti-inflammatory, and antioxidant activities. However, its effect on an organisms' longevity has not been thoroughly studied to date. Here, we report that 10 mg/mL IP supplementation significantly extended the lifespan of Drosophila . Additionally, IP enhanced flies' ability to resist environmental stress as estimated using starvation, paraquat, and desiccation assays. Additional experiments revealed insignificant changes in weight gain, physical activity, and metabolic profiles such as levels of water, lipid, and protein in flies receiving IP supplementation. Rather, levels of messenger RNA for enzymes that scavenge reactive oxygen species ( i.e. , superoxide dismutases, catalase, and glutathione peroxidase) were found to be significantly altered despite subtle changes in their catalytic activities. We hope that our research demonstrating IP-induced lifespan extension and related biological mechanisms of this interesting phenomenon will encourage further studies, which may eventually determine whether IP has utility as a novel antiaging agent.

2017

2017 · Biogerontology

Jujube (Ziziphus Jujuba Mill.) fruit feeding extends lifespan and increases tolerance to environmental stresses by regulating aging-associated gene expression in Drosophila

Saurav Ghimire, Man Su Kim

This publication investigates Jujube (Ziziphus Jujuba Mill.) fruit feeding extends lifespan and increases tolerance to environmental stresses by regulating aging-associated gene expression in Drosophila.

2015

2015 · Oxidative Medicine and Cellular Longevity

Enhanced locomotor activity is required to exert dietary restriction-dependent increase of stress resistance in Drosophila

Saurav Ghimire, Man Su Kim

Dietary restriction (DR) is known to be one of the most effective interventions to increase stress resistance, yet the mechanisms remain elusive. One of the most obvious DR-induced changes in phenotype is an increase in locomotor activity. Although it is conceptually perceivable that nutritional scarcity should prompt enhanced foraging behavior to garner additional dietary resources, the significance of enhanced movement activity has not been associated with the DR-dependent increase of stress resistance. In this study, we confirmed that flies raised on DR exhibited enhanced locomotive activity and increased stress resistance. Excision of fly wings minimized the DR-induced increase in locomotive activity, which resulted in attenuation of the DR-dependent increase of stress resistance. The possibility that wing clipping counteracts the DR by coercing flies to have more intake was ruled out since it did not induce any weight gain. Rather it was found that elimination of reactive oxygen species (ROS) that is enhanced by DR-induced upregulation of expression of antioxidant genes was significantly reduced by wing clipping. Collectively, our data suggests that DR increased stress resistance by increasing the locomotor activity, which upregulated expression of protective genes including, but not limited to, ROS scavenger system.

2015 · Biomolecules & Therapeutics

Defensive behavior against noxious heat stimuli is declined with aging due to decreased pain-associated gene expression in Drosophila

Saurav Ghimire, Man Su Kim

This publication investigates Defensive behavior against noxious heat stimuli is declined with aging due to decreased pain-associated gene expression in Drosophila.

2013

2013 · JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH

Evaluation of anti-secretory and anti-ulcerogenic activities of Avipattikar Churna on the peptic ulcers in experimental rats

Sudesh Gyawali

This publication investigates Evaluation of anti-secretory and anti-ulcerogenic activities of Avipattikar Churna on the peptic ulcers in experimental rats.