Biology subjects

Park, S.-K.

Publications and source records attributed to Park, S.-K..

17 recordsLinked to original sources

bioRxiv2026

Expression of TRPMPZQ in excitable cells and sensory structures throughout the Schistosoma mansoni lifecycle

Praziquantel (PZQ) is an essential medicine used to treat schistosomiasis and other infectious diseases caused by parasitic flatworms. The parasite target of PZQ is a transient receptor potential ion channel of the melastatin subfamily, TRPMPZQ. As little is currently known about the native role of TRPMPZQ in schistosomes, we developed and validated TRPMPZQ specific antibodies to immunolocalize TRPMPZQ across various S. mansoni life cycle stages (adult worms, juvenile worms, miracidia and cercariae). TRPMPZQ was expressed in muscle, nervous tissues, as well as various sensory structures on the surface of the parasite across all these life cycle stages. In adult male worms, TRPMPZQ positive neurons innervated the oral and ventral suckers as well as sensory papillae covering the head of the worm. TRPMPZQ was also present in papillae throughout the body, and within tubercles. In a S. mansoni strain selected in the laboratory for resistance to PZQ, reduced expression and immunostaining of TRPMPZQ was apparent. In immature worms, which can recover from PZQ exposure, TRPMPZQ expression was predominantly found within the musculature compared with the neuronal localization evident in adult worms. A developmental transition of TRPMPZQ from muscle to nervous tissues during schistosome maturation was also supported from single cell RNAseq data. Because muscle buffers Ca2+ transients more effectively than neurons, the transition of TRPMPZQ away from muscle during schistosome maturation may increase the sensitivity of adult male worms to PZQ.

microbiology↗

bioRxiv2026

A Continuum of Atrial Peristalsis Initiates the Bicuspid to Quadricuspid Valve Transition

How chamber-specific hemodynamic shear forces coordinate the spatial and temporal patterning of cardiac valves remains poorly understood. The zebrafish atrioventricular (AV) valve transitions from 2-cusp to 4-cusp at 14 days post-fertilization (dpf) through commissural remodeling, differential cell proliferation, and chondrogenic matrix secretion. Orthogonal valvular axes are present at 25 hpf (hours), preceding endocardial cushion formation. AV canal remodeling aligns the shear stress with leaflet formation at 48 hpf and 14 dpf. At 28 hpf, the ventricle develops functional syncytium, while the atrial peristalsis remains and is necessary for the Klf2a-Snai1b signaling in Notch-negative and ccm1-positive endocardial cells. Without atrial contraction, the 2-to 4-cusp transition (86.7%) fails to occur. In the absence of ventricular contraction and relaxation, the formation of the first pair of leaflets (100%) does not initiate. As a corollary, we demonstrate that KLF4/SNAI1 expression at the commissure is conserved in the mammalian AV 2- to 4-cushion transition.

developmental biology↗

bioRxiv2026

Photoaged microplastics disrupt endothelial stretch-sensitive ion channels to impair calcium signaling and vascular integrity

Plastic-derived micro- and nanoplastics are pervasive, but how environmentally aged particles affect vascular barriers is poorly understood. We hypothesized that photoaged plastics impair endothelial force-sensing, triggering gut-brain-heart barrier failure. Ultraviolet (UV) exposure converted pristine nanoplastics into oxidized, irregular photoaged microplastic aggregates (> 1.2 {micro}m). In human aortic endothelial cells, photoaged particles increased membrane stiffness and activated transcriptional programs linked to permeability, junction disruption, inflammation, and cytoskeletal remodeling. Mechanistically, photoaged particles selectively inhibited Piezo1-mediated Ca2+ signaling and downstream Notch activity without changing PIEZO1 expression, and endothelial CRISPR inhibition of PIEZO1 recapitulated these effects. In zebrafish, photoaged plastic exposure increased gut-vascular permeability and systemic spread with brain and heart accumulation, accompanied by reduced neurovascular and myocardial Ca2+ signals, depressed cardiac contractility, and abnormal locomotor behavior. Thus, photoaged plastics compromise vascular barriers through disrupted endothelial Piezo1-Notch mechanotransduction.

cell biology↗

bioRxiv2026

Clonazepam activates the transient receptor potential melastatin 8 (TRPM8) ion channel

Benzodiazepines represent a major class of drugs prescribed as treatments for anxiety, insomnia and seizures. They act by engaging GABAA receptors in the central nervous system to depress neuronal excitability. Here, the polypharmacology of benzodiazepines was explored by studying their engagement of human TRP channels revealing clonazepam acts as a robust and selective activator of the TRPM8 ion channel. Clonazepam-evoked Ca2+ signals were observed in cells expressing human TRPM8 channels, and in mouse trigeminal neurons. These responses were completely blocked by pharmacological or genetic inhibition of TRPM8 function. This discovery likely explains why clonazepam is an effective treatment for the painful oral condition known as burning mouth disorder, where local activation of TRPM8 channels in sensory neurons mitigates the painful symptoms of this disease.

neuroscience↗

bioRxiv2025

TRPtracker: a community database for monitoring praziquantel sensitivity at TRPMPZQ variants

The anthelmintic praziquantel (PZQ) has been used for decades as the clinical therapy for schistosomiasis, and remains the only available drug. As a cheap and effective drug therapy for all human disease-causing Schistosoma species, usage of PZQ underpins mass drug administration strategies aimed at eliminating schistosomiasis as a public health problem by 2030. Concern over the potential emergence of resistance to PZQ is therefore warranted, as it would constitute a major threat to this approach. In terms of molecular adaptations conferring PZQ resistance, variation in the sequence and/or expression of the drug target is an obvious mechanism and should be a priority for surveillance efforts. The target of PZQ is a transient receptor potential ion channel, TRPMPZQ, which is established as a locus that regulates schistosome sensitivity to PZQ. Here, we describe the establishment of a community resource, TRPtracker, which coalesces data on TRPMPZQ natural variants together with measurements of individual variant sensitivity to PZQ. A compendium of laboratory-generated mutants in TRPMPZQ is also compiled in TRPtracker to map regions within TRPMPZQ critical for PZQ sensitivity. Aggregation of data from multiple research groups into TRPtracker permits rapid community-wide exchange of data, cataloguing which TRPMPZQ variants have been functionally profiled, where geographically these variants have been found, their frequency within populations and their potential impact on PZQ sensitivity.

microbiology↗

bioRxiv2024

A model of inborn metabolism errors associated with adenine amyloid-like fiber formation reduces TDP-43 aggregation and toxicity in yeast

TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1{Delta} aah1{Delta} yeast model of disorders of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from a liquid-like, toward a more amyloid-like, state. At the same time the deletions reduce TDP-43s effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like and not amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1{Delta} aah1{Delta} deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine/TDP-43 fiber interactions as seen for other heterologous fibers. The work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.

genetics↗

bioRxiv2024

Extensive transmission and variation in a functional receptor for praziquantel resistance in endemic Schistosoma mansoni

Mass-drug administration (MDA) of human populations using praziquantel monotherapy has become the primary strategy for controlling and potentially eliminating the major neglected tropical disease schistosomiasis. To understand how long-term MDA impacts schistosome populations, we analysed whole-genome sequence data of 570 Schistosoma mansoni samples (and the closely related outgroup species, S. rodhaini) from eight countries incorporating both publicly-available sequence data and new parasite material. This revealed broad-scale genetic structure across countries but with extensive transmission over hundreds of kilometres. We characterised variation across the transient receptor potential melastatin ion channel, TRPMPZQ, a target of praziquantel, which has recently been found to influence praziquantel susceptibility. Functional profiling of TRPMPZQ variants found in endemic populations identified four mutations that reduced channel sensitivity to praziquantel, indicating standing variation for resistance. Analysis of parasite infrapopulations sampled from individuals pre- and post-treatment identified instances of treatment failure, further indicative of potential praziquantel resistance. As schistosomiasis is targeted for elimination as a public health problem by 2030 in all currently endemic countries, and even interruption of transmission in selected African regions, we provide an in-depth genomic characterisation of endemic populations and an approach to identify emerging praziquantel resistance alleles. One Sentence SummaryPopulation genomics and functional genetics of praziquantel resistance in Schistosoma mansoni

genomics↗

bioRxiv2023

Target-based discovery of a broad spectrum flukicide

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases - for example, the parasitic blood fluke infection, schistosomiasis - are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola. This is due to a single amino acid change within the target of PZQ, a transient receptor potential ion channel (TRPMPZQ), in Fasciola species. Here we identify benzamidoquinazolinone analogs that are active against Fasciola TRPMPZQ. Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and damage to the protective tegument of these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPMPZQ orthologs in all profiled species of parasitic fluke. This broad spectrum activity was manifest as BZQ adopts a pose within the binding pocket of TRPMPZQ dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQ and a first-in-class, broad spectrum flukicide.

microbiology↗

bioRxiv2023

Exercise Mitigates Flow Recirculation and Activates Mechanosensitive Transcriptome to Uncover Endothelial SCD1-Catalyzed Anti-Inflammatory Metabolites

Exercise modulates vascular plasticity in multiple organ systems; however, the metabolomic transducers underlying exercise and vascular protection in the disturbed flow-prone vasculature remain under-investigated. We simulated exercise-augmented pulsatile shear stress (PSS) to mitigate flow recirculation in the lesser curvature of the aortic arch. When human aortic endothelial cells (HAECs) were subjected to PSS ({tau}ave = 50 dyne{middle dot}cm-2, {partial}{tau}/{partial}t = 71 dyne{middle dot}cm-2{middle dot}s-1, 1 Hz), untargeted metabolomic analysis revealed that Stearoyl-CoA Desaturase (SCD1) in the endoplasmic reticulum (ER) catalyzed the fatty acid metabolite, oleic acid (OA), to mitigate inflammatory mediators. Following 24 hours of exercise, wild-type C57BL/6J mice developed elevated SCD1-catalyzed lipid metabolites in the plasma, including OA and palmitoleic acid (PA). Exercise over a 2-week period increased endothelial SCD1 in the ER. Exercise further modulated the time-averaged wall shear stress (TAWSS or{tau} ave) and oscillatory shear index (OSIave), upregulated Scd1 and attenuated VCAM1 expression in the disturbed flow-prone aortic arch in Ldlr-/- mice on high-fat diet but not in Ldlr-/-Scd1EC-/- mice. Scd1 overexpression via recombinant adenovirus also mitigated ER stress. Single cell transcriptomic analysis of the mouse aorta revealed interconnection of Scd1 with mechanosensitive genes, namely Irs2, Acox1 and Adipor2 that modulate lipid metabolism pathways. Taken together, exercise modulates PSS ({tau}ave and OSIave) to activate SCD1 as a metabolomic transducer to ameliorate inflammation in the disturbed flow-prone vasculature.

physiology↗

bioRxiv2021

Activating P2Y1 receptors improves function in arteries with repressed autophagy

ObjectiveThe importance of endothelial cell (EC) autophagy to vascular homeostasis is evolving. Earlier we reported that purinergic 2Y1 receptor (P2Y1-R) activation rejuvenates shearstress induced nitric oxide (NO) generation in bovine aortic endothelial cells that is otherwise compromised after pharmacological and genetic autophagy repression. Here we determined the translational and functional relevance of these findings. Approach and ResultsFirst we assessed translational relevance using older humans and mice that exhibit blunted EC autophagy at rest together with impaired arterial function vs. appropriate controls. Rhythmic handgrip exercise elevated radial artery shear rate similarly in adult and older males for 60-min. Compared to baseline, autophagy initiation, p-eNOSS1177 activation, and NO generation, occurred in radial artery ECs from adult but not older subjects. Regarding mice, indexes of autophagy and p-eNOSS1177 activation were robust in ECs from adult but not older mice in response to 60-min treadmill-running. Next we questioned whether an inability to initiate EC autophagy precipitates arterial dysfunction. Age-associated reductions in intraluminal flow-mediated vasodilation observed in older vs. adult mice were recapitulated in arteries from adult mice by : (i) NO synthase inhibition; (ii) autophagy impairment using 3-methyladenine (3-MA); (iii) EC Atg3 depletion (iecAtg3KO mice); (iv) P2Y1-R blockade; and (v) germline depletion of P2Y1-Rs. Importantly, P2Y1-R activation using 2-methylthio-ADP (2-Me-ADP) improved vasodilatory capacity in arteries from : (i) adult mice treated with 3-MA; (ii) adult iecAtg3KO mice; and (iii) older animals with repressed EC autophagy. ConclusionsArterial dysfunction concurrent with pharmacological, genetic, and age-associated EC autophagy compromise is improved by activating P2Y1-Rs.

physiology↗

bioRxiv2021

Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts.

ABSTRACT AND KEYWORDSThere is evidence for a progressive decline of protein quality control mechanisms during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy (referred to as autophagy) is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs adult mice. As expected, 24-month old male C57BL/6J mice (old) exhibited : (i) repressed autophagosome formation and protein aggregate accumulation in the heart; (ii) systolic and diastolic dysfunction; and (iii) reduced exercise capacity, vs. 8-month old (adult) mice (all p< .05). Separate cohorts of 21 month old mice completed a 3-month progressive resistance treadmill-running program (old-ETR) that improved (all < .05) : (i) body composition; (ii) exercise capacity; and (iii) soleus muscle citrate synthase activity, vs. age-matched mice that did not train (old-SED). Importantly, (iv) protein expression of autophagy markers indicated trafficking of the autophagosome to the lysosome increased, (v) protein aggregate clearance improved, and (vi) overall function was enhanced (all p<0.05), in hearts from old-ETR vs. old- SED mice. Dietary maneuvers and pharmacological interventions shown to elevate basal autophagy are reported to mitigate / reverse age-associated cardiac dysfunction. Here we show the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and overall function in mouse hearts.

physiology↗

bioRxiv2021

Mechanism of praziquantel action at a parasitic flatworm ion channel

Praziquantel (PZQ) is an essential medicine for treating parasitic flatworm infections such as schistosomiasis, which afflicts over 250 million people. However, PZQ is not universally effective, lacking activity against the liver fluke Fasciola. The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here, we show PZQ activates a transient receptor potential melastatin ion channel (TRPMPZQ) in schistosomes by engaging a hydrophobic ligand binding pocket within the voltage-sensor like domain to cause Ca2+ entry and worm paralysis. PZQ activates TRPMPZQ homologues in other PZQ-sensitive flukes, but not Fasciola. However, a single amino acid change in the Fasciola TRPMPZQ binding pocket, to mimic schistosome TRPMPZQ, confers PZQ sensitivity. After decades of clinical use, the basis of PZQ action at a druggable TRP channel is resolved.

pharmacology and toxicology↗

bioRxiv2020

Purging of deleterious mutations during domestication in the predominant selfing crop soybean

As a predominant plant protein and oil source for both food and feed, soybean is unique in that both domesticated and wild types are predominantly selfing. Here we present a genome-wide variation map of 781 soybean accessions that include 418 domesticated (Glycine max) and 345 wild (Glycine soja) accessions and 18 of their natural hybrids. We identified 10.5 million single nucleotide polymorphisms and 5.7 million small indels that contribute to within- and between-population variations. We describe improved detection of domestication-selective sweeps and drastic reduction of overall deleterious alleles in domesticated soybean relative to wild soybean in contrast to the cost of domestication hypothesis. This resource enables the marker density of existing data sets to be increased to improve the resolution of association studies.

genomics↗

bioRxiv2019

Significantly different expression levels of microRNAs associated with vascular invasion in hepatocellular carcinoma and their prognostic significance after surgical resection

BackgroundAlthough gross vascular invasion (VI) has prognostic significance in patients with hepatocellular carcinoma (HCC) who have undergone hepatic resection, few studies have investigated the relationship between gross VI and aberrant expression of microribonucleic acids (miRNAs and miRs). Thus, the objective of this study was to identify miRNAs selectively expressed in HCC with gross VI and investigate their prognostic significance.\n\nMaterials and MethodsEligible two datasets (accession number: GSE20594 and GSE67140) were collected from the National Center for Biotechnology Informations (NCBI) Gene Expression Omnibus (GEO) database to compare miRNAs expression between HCC with and without gross VI. Differentially expressed miRNAs were externally validated using expression data from The Cancer Genome Atlas (TCGA) database. Prognostic significance and predicted functions of selected miRNAs for HCC were also investigated.\n\nResultsThirty-five miRNAs were differentially expressed between HCC with and without gross VI in both datasets. Among them, four miRNAs were validated using TCGA database. miR-582 was upregulated to a greater extent while miR-99a, miR-100, and miR-148a were downregulated to a greater extent in patients with HCC and gross VI than in those with HCC but no VI. Receiver operating characteristic (ROC) curve analysis showed discriminatory power of these miRNAs in predicting gross VI. Multivariate survival analysis revealed that types of surgery, advanced tumor node metastasis (TNM) stage, and miR-100 underexpression were independently associated with tumor recurrence. It also revealed that types of surgery, advanced TNM stage, miR-100 underexpression, and miR-582 overexpression were independent risk factors for overall survival (OS) after hepatic resection for HCC. A text mining analysis revealed that these miRNAs were linked to multifaceted hallmarks of cancer, including \"invasion and metastasis.\"\n\nConclusionsmiR-100 underexpression and miR-582 overexpression were associated with gross VI and poor survival of patients after hepatic resection for HCC.

cancer biology↗

bioRxiv2018

An assessment of the interactions between climatic conditions and genetic characteristic on the agricultural performance of soybeans grown in Northeast Asia

Glycine max, commonly known as soybean or soya bean, is a species of legume native to East Asia. The interactions between climatic conditions and genetic characteristic affect the agricultural performance of soybean. Therefore, an investigation to identify the main elements affecting the agricultural performances of 11 soybeans was conducted in Northeast Asia, China [Harbin (45{degrees}12'N) Yanji (42{degrees}53'N) Dalian (39{degrees}30'N) Qingdao (36{degrees}26'N)] Republic of Korea [Suwon (37{degrees}16'N) and Jeonju (35{degrees}49'N)]. The days to flowering (DTF) of soybeans with the e1-nf and e1-as alleles and the E1e2e3e4 genotype, except Keumgangkong, Tawonkong, and Duyoukong, was relatively short compared to soybeans with other alleles. Although DTF of the soybeans was highly correlated to all climatic conditions, days to maturity (DTM) and 100-seed weight (HSW) of the soybeans showed no significant correlation with any climatic conditions. The soybeans with a dominant Dt1 allele, except Tawonkong, had the longest stem length (STL). Moreover, the STL of the soybeans grown at the test fields showed a positive correlation with only day length (DL) although the results of our chamber test showed that STL of soybean was positively affected by average temperature (AVT) and DL. Soybean yield (YLD) showed positive correlations with latitude and DL (except L62-667, OT89-5, and OT89-6) although the response of YLD to the climatic conditions was cultivar-specific. Our results show that DTF and STL of soybeans grown in Northeast Asia are highly affected by DL although AVT and genetic characteristic also affect DTF and STL. Along with these results, we confirmed that the DTM, HSW, and YLD of the soybeans vary in relation to their genetic characteristic.

plant biology↗

bioRxiv2018

TDP-43 is more toxic in respiring than in non-respiring cells, but respiration is not absolutely required for TDP-43 toxicity.

The trans-activating response DNA-binding protein 43 (TDP-43) is a transcriptional repressor and splicing factor. TDP-43 is normally mostly in the nucleus, although it shuttles to the cytoplasm. Mutations in TDP-43 are one cause of familial amyotrophic lateral sclerosis (ALS). In neurons of these patients, TDP-43 forms cytoplasmic aggregates. In addition, wild-type TDP-43 is also frequently found in neuronal cytoplasmic aggregates in patients with neurodegenerative diseases not caused by TDP-43 mutations. TDP-43 expressed in yeast causes toxicity and forms cytoplasmic aggregates. This disease model has been validated because genetic modifiers of TDP-43 toxicity in yeast have led to the discovery that conserved genes in humans are ALS genetic risk factors. While it is still unknown how TDP-43 is associated with toxicity, several studies find that TDP-43 alters mitochondrial function. We now report that TDP-43 is much more toxic when yeast is grown in non-fermentable media requiring respiration than when grown on fermentable carbon sources. However, we also establish that TDP-43 remains toxic in the absence of respiration. Thus, there is a TDP-43 toxicity target in yeast distinct from respiration and respiration is not required for this toxicity. Since we find that H2O2 increases the toxicity of TDP-43, the free oxygen radicals associated with respiration could likewise enhance the toxicity of TDP-43. In this case, the TDP-43 toxicity targets in the presence or absence of respiration could be identical, with the free radical oxygen species produced by respiration activating TDP-43 to become more toxic or making TDP-43 targets more vulnerable.\n\nHighlightsO_LITDP-43 toxicity and aggregation is enhanced when yeast are grown in media that requires respiration.\nC_LIO_LIRespiration is not the sole target of TDP-43 toxicity because TDP-43 still aggregates and is toxic in cells that are not respiring.\nC_LIO_LIHydrogen peroxide enhances TDP-43 toxicity in the absence of respiration suggesting that reactive oxygen species (ROS) produced by respiration may likewise enhance TDP-43 toxicity.\nC_LIO_LIROS could activate TDP-43 to become more toxic or make TDP-43 targets more vulnerable.\nC_LI\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/415893_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@85d24aorg.highwire.dtl.DTLVardef@1b103d3org.highwire.dtl.DTLVardef@72280dorg.highwire.dtl.DTLVardef@a3a82e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2018

A yeast model of calcium-responsive transactivator protein (CREST) proteinopathy shows that PBP1/ATXN2 modifies CREST aggregation and toxicity.

Proteins associated with familial neurodegenerative disease often aggregate in patients neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1, reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral sclerosis (ALS) risk factor and therapeutic target. Likewise, new yeast neurodegenerative disease models could facilitate identification of other risk factors and targets. Mutations in SS18L1, encoding the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS. We show that CREST is toxic in yeast and forms nuclear and occasionally cytoplasmic foci that stain with Thioflavin-T, a dye indicative of amyloid-like protein. Like the yeast chromatin-remodeling factor SWI1, CREST inhibits silencing of FLO genes. Toxicity of CREST is enhanced by the [PIN+] prion and reduced by deletion of the HSP104 chaperone required for the propagation of many yeast prions. Likewise, deletion of PBP1 reduced CREST toxicity and aggregation. In accord with the yeast data, we show that the Drosophila ortholog of human ATXN2, dAtx2, is a potent enhancer of CREST toxicity. Downregulation of dAtx2 in flies overexpressing CREST in retinal ganglion cells was sufficient to largely rescue the severe degenerative phenotype induced by human CREST. Overexpression caused considerable co-localization of CREST and PBP1/ATXN2 in cytoplasmic foci in both yeast and mammalian cells. Thus, co-aggregation of CREST and PBP1/ATXN2 may serve as one of the mechanisms of PBP1/ATXN2-mediated toxicity. These results extend the spectrum of ALS associated proteins whose toxicity is regulated by PBP1/ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.\n\nAuthor summaryMutations in the calcium-responsive transactivator (CREST) protein have been shown to cause amyotrophic lateral sclerosis (ALS). Here we show that the human CREST protein expressed in yeast forms largely nuclear aggregates and is toxic. We also show that the HSP104 chaperone required for propagation of yeast prions is likewise required for CREST toxicity. Furthermore deletion of HSP104 affects CREST aggregation. ATXN2, previously shown to modify ALS toxicity caused by mutations in the TDP-43 encoding gene, also modifies toxicity of CREST expressed in either yeast or flies. In addition, deletion of the yeast ATXN2 ortholog reduces CREST aggregation. These results extend the spectrum of ALS associated proteins whose toxicity is regulated by ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.

molecular biology↗