Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity.

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurotoxicity.

Integration of transcriptome-wide association study with neuronal dysfunction assays provides functional genomics evidence for Parkinson's disease genes.

Genome-wide association studies (GWAS) have markedly advanced our understanding of the genetics of Parkinson's disease (PD), but they currently do not account for the full heritability of PD. In many cases it is difficult to unambiguously identify a specific gene within each locus because GWAS does not provide functional information on the identified candidate loci. Here we present an integrative approach that combines transcriptome-wide association study (TWAS) with high-throughput neuronal dysfunction analyses in Drosophila to discover and validate candidate PD genes. We identified 160 candidate genes whose misexpression is associated with PD risk via TWAS. Candidates were validated using orthogonal in silico methods and found to be functionally related to PD-associated pathways (i.e. endolysosome). We then mimicked these TWAS-predicted transcriptomic alterations in a Drosophila PD model and discovered that 50 candidates can modulate α-Synuclein(α-Syn)-induced neurodegeneration, allowing us to nominate new genes in previously known PD loci. We also uncovered additional novel PD candidate genes within GWAS suggestive loci (e.g. TTC19, ADORA2B, LZTS3, NRBP1, HN1L), which are also supported by clinical and functional evidence. These findings deepen our understanding of PD, and support applying our integrative approach to other complex trait disorders.

An altered extracellular matrix-integrin interface contributes to Huntington's disease-associated CNS dysfunction in glial and vascular cells.

Astrocytes and brain endothelial cells are components of the neurovascular unit that comprises the blood-brain barrier (BBB) and their dysfunction contributes to pathogenesis in Huntington's disease (HD). Defining the contribution of these cells to disease can inform cell-type-specific effects and uncover new disease-modifying therapeutic targets. These cells express integrin (ITG) adhesion receptors that anchor the cells to the extracellular matrix (ECM) to maintain the integrity of the BBB. We used HD patient-derived induced pluripotent stem cell (iPSC) modeling to study the ECM-ITG interface in astrocytes and brain microvascular endothelial cells and found ECM-ITG dysregulation in human iPSC-derived cells that may contribute to the dysfunction of the BBB in HD. This disruption has functional consequences since reducing ITG expression in glia in an HD Drosophila model suppressed disease-associated CNS dysfunction. Since ITGs can be targeted therapeutically and manipulating ITG signaling prevents neurodegeneration in other diseases, defining the role of ITGs in HD may provide a novel strategy of intervention to slow CNS pathophysiology to treat HD.

Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1.

A critical question in neurodegeneration is why the accumulation of disease-driving proteins causes selective neuronal loss despite their brain-wide expression. In Spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded Ataxin-1 (ATXN1) causes selective degeneration of cerebellar and brainstem neurons. Previous studies revealed that inhibiting Msk1 reduces phosphorylation of ATXN1 at S776 as well as its levels leading to improved cerebellar function. However, there are no regulators that modulate ATXN1 in the brainstem-the brain region whose pathology is most closely linked to premature death. To identify new regulators of ATXN1, we performed genetic screens and identified a transcription factor-kinase axis (ZBTB7B-RSK3) that regulates ATXN1 levels. Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems where it regulates Atxn1 by phosphorylating S776. Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model. Our results demonstrate that selective vulnerability of brain regions in SCA1 is governed by region-specific regulators of ATXN1, and targeting multiple regulators could rescue multiple degenerating brain areas.

Suppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide.

Identifying inhibitors of pathogenic proteins is the major strategy of targeted drug discoveries. This strategy meets challenges in targeting neurodegenerative disorders such as Huntington's disease (HD), which is mainly caused by the mutant huntingtin protein (mHTT), an "undruggable" pathogenic protein with unknown functions. We hypothesized that some of the chemical binders of mHTT may change its conformation and/or stability to suppress its downstream toxicity, functioning similarly to an "inhibitor" under a broader definition. We identified 21 potential mHTT selective binders through a small-molecule microarray­based screening. We further tested these compounds using secondary phenotypic screens for their effects on mHTT-induced toxicity and revealed four potential mHTT-binding compounds that may rescue HD-relevant phenotypes. Among them, a Food and Drug Administration­approved drug, desonide, was capable of suppressing mHTT toxicity in HD cellular and animal models by destabilizing mHTT through enhancing its polyubiquitination at the K6 site. Our study reveals the therapeutic potential of desonide for HD treatment and provides the proof of principle for a drug discovery pipeline: target-binder screens followed by phenotypic validation and mechanistic studies.

SPA-STOCSY: an automated tool for identifying annotated and non-annotated metabolites in high-throughput NMR spectra.

MOTIVATION: Nuclear magnetic resonance spectroscopy (NMR) is widely used to analyze metabolites in biological samples, but the analysis requires specific expertise, it is time-consuming, and can be inaccurate. Here, we present a powerful automate tool, SPatial clustering Algorithm-Statistical TOtal Correlation SpectroscopY (SPA-STOCSY), which overcomes challenges faced when analyzing NMR data and identifies metabolites in a sample with high accuracy. RESULTS: As a data-driven method, SPA-STOCSY estimates all parameters from the input dataset. It first investigates the covariance pattern among datapoints and then calculates the optimal threshold with which to cluster datapoints belonging to the same structural unit, i.e. the metabolite. Generated clusters are then automatically linked to a metabolite library to identify candidates. To assess SPA-STOCSY's efficiency and accuracy, we applied it to synthesized spectra and spectra acquired on Drosophila melanogaster tissue and human embryonic stem cells. In the synthesized spectra, SPA outperformed Statistical Recoupling of Variables (SRV), an existing method for clustering spectral peaks, by capturing a higher percentage of the signal regions and the close-to-zero noise regions. In the biological data, SPA-STOCSY performed comparably to the operator-based Chenomx analysis while avoiding operator bias, and it required <7 min of total computation time. Overall, SPA-STOCSY is a fast, accurate, and unbiased tool for untargeted analysis of metabolites in the NMR spectra. It may thus accelerate the use of NMR for scientific discoveries, medical diagnostics, and patient-specific decision making. AVAILABILITY AND IMPLEMENTATION: The codes of SPA-STOCSY are available at https://github.com/LiuzLab/SPA-STOCSY.

Spinocerebellar Ataxia Type 1 protein Ataxin-1 is signaled to DNA damage by ataxia-telangiectasia mutated kinase.

Spinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the ataxin-1 protein. Recent genetic correlational studies have implicated DNA damage repair pathways in modifying the age at onset of disease symptoms in SCA1 and Huntington's Disease, another polyglutamine expansion disease. We demonstrate that both endogenous and transfected ataxin-1 localizes to sites of DNA damage, which is impaired by polyglutamine expansion. This response is dependent on ataxia-telangiectasia mutated (ATM) kinase activity. Further, we characterize an ATM phosphorylation motif within ataxin-1 at serine 188. We show reduction of the Drosophila ATM homolog levels in a ATXN1[82Q] Drosophila model through shRNA or genetic cross ameliorates motor symptoms. These findings offer a possible explanation as to why DNA repair was implicated in SCA1 pathogenesis by past studies. The similarities between the ataxin-1 and the huntingtin responses to DNA damage provide further support for a shared pathogenic mechanism for polyglutamine expansion diseases.

Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease.

An early hallmark of Alzheimer's disease is the accumulation of amyloid-ß (Aß), inspiring numerous therapeutic strategies targeting this peptide. An alternative approach is to destabilize the amyloid beta precursor protein (APP) from which Aß is derived. We interrogated innate pathways governing APP stability using a siRNA screen for modifiers whose own reduction diminished APP in human cell lines and transgenic Drosophila. As proof of principle, we validated PKCß-a known modifier identified by the screen-in an APP transgenic mouse model. PKCß was genetically targeted using a novel adeno-associated virus shuttle vector to deliver microRNA-adapted shRNA via intracranial injection. In vivo reduction of PKCß initially diminished APP and delayed plaque formation. Despite persistent PKCß suppression, the effect on APP and amyloid diminished over time. Our study advances this approach for mining druggable modifiers of disease-associated proteins, while cautioning that prolonged in vivo validation may be needed to reveal emergent limitations on efficacy.

Harnessing the paradoxical phenotypes of APOE ɛ2 and APOE ɛ4 to identify genetic modifiers in Alzheimer's disease.

The strongest genetic risk factor for idiopathic late-onset Alzheimer's disease (LOAD) is apolipoprotein E (APOE) ɛ4, while the APOE ɛ2 allele is protective. However, there are paradoxical APOE ɛ4 carriers who remain disease-free and APOE ɛ2 carriers with LOAD. We compared exomes of healthy APOE ɛ4 carriers and APOE ɛ2 Alzheimer's disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau- or ß42-induced neurodegeneration in Drosophila. Variants in these genes were associated with AD risk, even in APOE ɛ3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type-specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available.

PAK1 regulates ATXN1 levels providing an opportunity to modify its toxicity in spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 (SCA1) is caused by the expansion of a trinucleotide repeat that encodes a polyglutamine tract in ataxin-1 (ATXN1). The expanded polyglutamine in ATXN1 increases the protein's stability and results in its accumulation and toxicity. Previous studies have demonstrated that decreasing ATXN1 levels ameliorates SCA1 phenotypes and pathology in mouse models. We rationalized that reducing ATXN1 levels through pharmacological inhibition of its modulators could provide a therapeutic avenue for SCA1. Here, through a forward genetic screen in Drosophila we identified, p21-activated kinase 3 (Pak3) as a modulator of ATXN1 levels. Loss-of-function of fly Pak3 or Pak1, whose mammalian homologs belong to Group I of PAK proteins, reduces ATXN1 levels, and accordingly, improves disease pathology in a Drosophila model of SCA1. Knockdown of PAK1 potently reduces ATXN1 levels in mammalian cells independent of the well-characterized S776 phosphorylation site (known to stabilize ATXN1) thus revealing a novel molecular pathway that regulates ATXN1 levels. Furthermore, pharmacological inhibition of PAKs decreases ATXN1 levels in a mouse model of SCA1. To explore the potential of using PAK inhibitors in combination therapy, we combined the pharmacological inhibition of PAK with MSK1, a previously identified modulator of ATXN1, and examined their effects on ATXN1 levels. We found that inhibition of both pathways results in an additive decrease in ATXN1 levels. Together, this study identifies PAK signaling as a distinct molecular pathway that regulates ATXN1 levels and presents a promising opportunity to pursue for developing potential therapeutics for SCA1.

Two Isostructural URJC-4 Materials: From Hydrogen Physisorption to Heterogeneous Reductive Amination through Hydrogen Molecule Activation at Low Pressure.

Herein, two novel isostructural metal-organic frameworks (MOFs) M-URJC-4 (M = Co, Ni; URJC = "Universidad Rey Juan Carlos") with open metal sites, permanent microposity, and large surface areas and pore volumes have been developed. These novel MOFs, with polyhedral morphology, crystallize in the monoclinic P21/c space group, exhibiting a three-dimensional structure with microporous channels along the c axis. Initially, they were fully characterized and tested in hydrogen (H2) adsorption at different conditions of temperature and pressure. The physisorption capacities of both materials surpassed the gravimetric H2 uptake shown by most MOF materials under the same conditions. On the basis of the outstanding adsorption properties, the Ni-URJC-4 material was used as a catalyst in a one-pot reductive amination reaction using various carbonyl compounds and primary amines. A possible chemical pathway to obtain secondary amines was proposed via imine formation, and remarkable performances were accomplished. This work evidences the dual ability of M-URJC-4 materials to be used as a H2 adsorbent and a catalyst in reductive amination reactions, activating molecular H2 at low pressures for the reduction of C═N double bonds and providing reference structural features for the design of new versatile heterogeneous materials for industrial application.

A Druggable Genome Screen Identifies Modifiers of α-Synuclein Levels via a Tiered Cross-Species Validation Approach.

Accumulation of α-Synuclein (α-Syn) causes Parkinson's disease (PD) as well as other synucleopathies. α-Syn is the major component of Lewy bodies and Lewy neurites, the proteinaceous aggregates that are a hallmark of sporadic PD. In familial forms of PD, mutations or copy number variations in SNCA (the α-Syn gene) result in a net increase of its protein levels. Furthermore, common risk variants tied to PD are associated with small increases of wild-type α-Syn levels. These findings are further bolstered by animal studies which show that overexpression of α-Syn is sufficient to cause PD-like features. Thus, increased α-Syn levels are intrinsically tied to PD pathogenesis and underscore the importance of identifying the factors that regulate its levels. In this study, we establish a pooled RNAi screening approach and validation pipeline to probe the druggable genome for modifiers of α-Syn levels and identify 60 promising targets. Using a cross-species, tiered validation approach, we validate six strong candidates that modulate α-Syn levels and toxicity in cell lines, Drosophila, human neurons, and mouse brain of both sexes. More broadly, this genetic strategy and validation pipeline can be applied for the identification of therapeutic targets for disorders driven by dosage-sensitive proteins.SIGNIFICANCE STATEMENT We present a research strategy for the systematic identification and validation of genes modulating the levels of α-Synuclein, a protein involved in Parkinson's disease. A cell-based screen of the druggable genome (>7,500 genes that are potential therapeutic targets) yielded many modulators of α-Synuclein that were subsequently confirmed and validated in Drosophila, human neurons, and mouse brain. This approach has broad applicability to the multitude of neurological diseases that are caused by mutations in genes whose dosage is critical for brain function.

Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation.

Cleavage of mutant huntingtin (HTT) is an essential process in Huntington's disease (HD), an inherited neurodegenerative disorder. Cleavage generates N-ter fragments that contain the polyQ stretch and whose nuclear toxicity is well established. However, the functional defects induced by cleavage of full-length HTT remain elusive. Moreover, the contribution of non-polyQ C-terminal fragments is unknown. Using time- and site-specific control of full-length HTT proteolysis, we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies. Surprisingly, in addition to the canonical pathogenic N-ter fragments, the C-ter fragments generated, that do not contain the polyQ stretch, induced toxicity via dilation of the endoplasmic reticulum (ER) and increased ER stress. C-ter HTT bound to dynamin 1 and subsequently impaired its activity at ER membranes. Our findings support a role for HTT on dynamin 1 function and ER homoeostasis. Proteolysis-induced alteration of this function may be relevant to disease.

Novel and Versatile Cobalt Azobenzene-Based Metal-Organic Framework as Hydrogen Adsorbent.

A novel URJC-3 material based on cobalt and 5,5'-(diazene-1,2-diyl)diisophthalate ligand, containing Lewis acid and basic sites, has been synthesized under solvothermal conditions. Compound URJC-3, with polyhedral morphology, crystallizes in the tetragonal and P43 21 2 space group, exhibiting a three-dimensional structure with small channels along a and b axes. This material was fully characterized, and its hydrogen adsorption properties were estimated for a wide range of temperatures (77-298 K) and pressures (1-170 bar). The hydrogen storage capacity of URJC-3 is quite high in relation to its moderate surface area, which is probably due to the confinement effect of hydrogen molecules inside its reduced pores of 6 Å, which is close the ionic radii of hydrogen molecules. The storage capacity of this material is not only higher than that of active carbon and purified single-walled carbon nanotubes, but also surpasses the gravimetric hydrogen uptake of most MOF materials.

RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1.

Many neurodegenerative disorders, such as Alzheimer's, Parkinson's and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein's resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS-MAPK-MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases.

Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.

We report the identification and characterization of a previously unknown suppressor of myopathy caused by expansion of CUG repeats, the mutation that triggers Myotonic Dystrophy Type 1 (DM1). We screened a collection of genes encoding RNA-binding proteins as candidates to modify DM1 pathogenesis using a well established Drosophila model of the disease. The screen revealed smaug as a powerful modulator of CUG-induced toxicity. Increasing smaug levels prevents muscle wasting and restores muscle function, while reducing its function exacerbates CUG-induced phenotypes. Using human myoblasts, we show physical interactions between human Smaug (SMAUG1/SMAD4A) and CUGBP1. Increased levels of SMAUG1 correct the abnormally high nuclear accumulation of CUGBP1 in myoblasts from DM1 patients. In addition, augmenting SMAUG1 levels leads to a reduction of inactive CUGBP1-eIF2α translational complexes and to a correction of translation of MRG15, a downstream target of CUGBP1. Therefore, Smaug suppresses CUG-mediated muscle wasting at least in part via restoration of translational activity of CUGBP1.

A genome-scale RNA-interference screen identifies RRAS signaling as a pathologic feature of Huntington's disease.

A genome-scale RNAi screen was performed in a mammalian cell-based assay to identify modifiers of mutant huntingtin toxicity. Ontology analysis of suppressor data identified processes previously implicated in Huntington's disease, including proteolysis, glutamate excitotoxicity, and mitochondrial dysfunction. In addition to established mechanisms, the screen identified multiple components of the RRAS signaling pathway as loss-of-function suppressors of mutant huntingtin toxicity in human and mouse cell models. Loss-of-function in orthologous RRAS pathway members also suppressed motor dysfunction in a Drosophila model of Huntington's disease. Abnormal activation of RRAS and a down-stream effector, RAF1, was observed in cellular models and a mouse model of Huntington's disease. We also observe co-localization of RRAS and mutant huntingtin in cells and in mouse striatum, suggesting that activation of R-Ras may occur through protein interaction. These data indicate that mutant huntingtin exerts a pathogenic effect on this pathway that can be corrected at multiple intervention points including RRAS, FNTA/B, PIN1, and PLK1. Consistent with these results, chemical inhibition of farnesyltransferase can also suppress mutant huntingtin toxicity. These data suggest that pharmacological inhibition of RRAS signaling may confer therapeutic benefit in Huntington's disease.

Intensified-Fenton process for the treatment of phenol aqueous solutions.

An intensified-Fenton process for the treatment of phenol aqueous solutions has been studied as a continuous catalytic wet hydrogen peroxide oxidation system. This process consists of coupling the catalytic activity of a heterogeneous Fenton-like catalyst with the homogeneous contribution of its dissolved iron species. Agglomerated mesoporous SBA-15 silica-supported iron oxide (Fe2O3/SBA-15) material was used as heterogeneous catalyst. The influence of the reaction temperature and the initial hydrogen peroxide dosages was studied in order to minimize the operation cost of the process. The catalytic performance of the process was assessed in terms of total organic carbon (TOC) and hydrogen peroxide conversions. Likewise, the stability of the solid Fenton-like catalyst was also evaluated in terms of the dissolved iron species. The increase of the reaction temperature enhanced the TOC conversion and reduced the iron leaching from the heterogeneous catalyst. These results were related to the degradation of oxalic acid as responsible for iron extraction by formation of soluble stable iron complexes into the aqueous medium. Finally, the use of a moderate hydrogen peroxide concentration (2.6 g/L) and milder temperatures (80-120 °C) has led to remarkable results of TOC and phenol reductions as well as oxidant efficiency through the intensified-Fenton process.

Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy.

Neuronal network hyperexcitability underlies the pathogenesis of seizures and is a component of some degenerative neurological disorders such as Alzheimer's disease (AD). Recently, the microtubule-binding protein tau has been implicated in the regulation of network synchronization. Genetic removal of Mapt, the gene encoding tau, in AD models overexpressing amyloid-ß (Aß) decreases hyperexcitability and normalizes the excitation/inhibition imbalance. Whether this effect of tau removal is specific to Aß mouse models remains to be determined. Here, we examined tau as an excitability modifier in the non-AD nervous system using genetic deletion of tau in mouse and Drosophila models of hyperexcitability. Kcna1(-/-) mice lack Kv1.1-delayed rectifier currents and exhibit severe spontaneous seizures, early lethality, and megencephaly. Young Kcna1(-/-) mice retained wild-type levels of Aß, tau, and tau phospho-Thr(231). Decreasing tau in Kcna1(-/-) mice reduced hyperexcitability and alleviated seizure-related comorbidities. Tau reduction decreased Kcna1(-/-) video-EEG recorded seizure frequency and duration as well as normalized Kcna1(-/-) hippocampal network hyperexcitability in vitro. Additionally, tau reduction increased Kcna1(-/-) survival and prevented megencephaly and hippocampal hypertrophy, as determined by MRI. Bang-sensitive Drosophila mutants display paralysis and seizures in response to mechanical stimulation, providing a complementary excitability assay for epistatic interactions. We found that tau reduction significantly decreased seizure sensitivity in two independent bang-sensitive mutant models, kcc and eas. Our results indicate that tau plays a general role in regulating intrinsic neuronal network hyperexcitability independently of Aß overexpression and suggest that reducing tau function could be a viable target for therapeutic intervention in seizure disorders and antiepileptogenesis.

Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases.

Nuclear dysfunction is a key feature of the pathology of polyglutamine (polyQ) diseases. It has been suggested that mutant polyQ proteins impair functions of nuclear factors by interacting with them directly in the nucleus. However, a systematic analysis of quantitative changes in soluble nuclear proteins in neurons expressing mutant polyQ proteins has not been performed. Here, we perform a proteome analysis of soluble nuclear proteins prepared from neurons expressing huntingtin (Htt) or ataxin-1 (AT1) protein, and show that mutant AT1 and Htt similarly reduce the concentration of soluble high mobility group B1/2 (HMGB1/2) proteins. Immunoprecipitation and pulldown assays indicate that HMGBs interact with mutant AT1 and Htt. Immunohistochemistry showed that these proteins were reduced in the nuclear region outside of inclusion bodies in affected neurons. Compensatory expression of HMGBs ameliorated polyQ-induced pathology in primary neurons and in Drosophila polyQ models. Furthermore, HMGBs repressed genotoxic stress signals induced by mutant Htt or transcriptional repression. Thus, HMGBs may be critical regulators of polyQ disease pathology and could be targets for therapy development.