IL-4/STAT6 axis observed to reverse proliferative defect in SCA3 patient-derived neural progenitor cells.

Spinocerebellar ataxia 3 (SCA3) is an incurable, neurodegenerative genetic disorder that leads to progressive cerebellar ataxia and other parkinsonian-like pathologies because of loss of cerebellar neurons. The role of an expanded polyglutamine aggregate on neural progenitor cells is unknown. Here, we show that SCA3 patient-specific induced neural progenitor cells (iNPCs) exhibit proliferative defects. Moreover, SCA3 iNPCs have reduced autophagic expression compared to control. Furthermore, although SCA3 iNPCs continue to proliferate, they do not survive subsequent passages compared to control iNPCs, indicating the likelihood that SCA3 iNPCs undergo rapid senescence. Exposure to interleukin-4 (IL-4), a type 2 cytokine produced by immune cells, resulted in an observed increase in expression of autophagic programs and a reduction in the proliferation defect observed in SCA3 iNPCs. Our results indicate a previously unobserved role of SCA3 disease ontology on the neural stem cell pool and a potential therapeutic strategy using IL-4 to ameliorate or delay disease pathology in the SCA3 neural progenitor cell population.

Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/ß-catenin pathway in C9ALS/FTD.

The GGGGCC hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C9orf72) gene is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). In this study, we demonstrate that the zinc finger (ZF) transcriptional regulator Yin Yang 1 (YY1) binds to the promoter region of the planar cell polarity gene Fuzzy to regulate its transcription. We show that YY1 interacts with GGGGCC repeat RNA via its ZF and that this interaction compromises the binding of YY1 to the FuzzyYY1 promoter sites, resulting in the downregulation of Fuzzy transcription. The decrease in Fuzzy protein expression in turn activates the canonical Wnt/ß-catenin pathway and induces synaptic deficits in C9ALS/FTD neurons. Our findings demonstrate a C9orf72 GGGGCC RNA-initiated perturbation of YY1-Fuzzy transcriptional control that implicates aberrant Wnt/ß-catenin signalling in C9ALS/FTD-associated neurodegeneration. This pathogenic cascade provides a potential new target for disease-modifying therapy.

Communicating science in the COVID-19 news in the UK during Omicron waves: exploring representations of nature of science with epistemic network analysis.

News media plays a vital role in communicating scientific evidence to the public during the COVID-19 pandemic. Such communication is important for convincing the public to follow social distancing guidelines and to respond to health campaigns such as vaccination programmes. However, newspapers were criticised that they focus on the socio-political perspective of science, without explaining the nature of scientific works behind the government's decisions. This paper examines the connections of the nature of science categories in the COVID-19 era by four local newspapers in the United Kingdom between November 2021 to February 2022. Nature of science refers to different aspects of how science works such as aims, values, methods and social institutions of science. Considering the news media may mediate public information and perception of scientific stories, it is relevant to ask how the various British newspapers covered aspects of science during the pandemic. In the period explored, Omicron variant was initially a variant of concern, and an increasing number of scientific evidence showed that the less severity of this variant might move the country from pandemic to endemic. We explored how news articles communicate public health information by addressing how science works during the period when Omicron variants surge. A novel discourse analysis approach, epistemic network analysis is used to characterise the frequency of connections of categories of the nature of science. The connection between political factors and the professional activities of scientists, as well as that with scientific practices are more apparent in left-populated and centralist outlets than in right-populated news outlets. Among four news outlets across the political spectrum, a left-populated newspaper, the Guardian, is not consistent in representing relations of different aspects of the nature of scientific works across different stages of the public health crisis. Inconsistency of addressing aspects of scientific works and a downplay of the cognitive-epistemic nature of scientific works likely lead to failure in trust and consumption of scientific knowledge by the public in the healthcare crisis.

Word reading transfer in two distinct languages in reading interventions: How Chinese-English bilingual children with reading difficulties learn to read.

PURPOSE: Skills developed from literacy training in L1 are shown to transfer to reading in L2 when both languages involve an alphabetic writing system. However, transfer of literacy skills between a logographic L1 and an alphabetic L2 is less studied. This study examined whether the gain in literacy skills after an 8-week training on 1) Chinese character recognition or 2) English phonics, may generalize across the two languages in Chinese elementary students with reading disabilities. METHODS: Chinese-speaking students identified with reading difficulties were randomly assigned to the Chinese intervention (Chinese character orthography training), English intervention (English phonics training), and control groups. Their Chinese and English literacy skills were measured before and after the interventions. RESULTS: Though training on the orthography of Chinese characters significantly improved performance in Chinese word reading and Chinese orthographic awareness, our results did not provide evidence for the generalization of word-decoding skills from L1 Chinese to word reading in L2 English. However, phonics training in L2 English benefitted not only English word reading, but also cross-language word reading in L1 Chinese. CONCLUSION: We postulated that teaching children analytical skills in decoding words in an alphabetic writing system might likewise benefit their word decoding in a logographic script.

Chronic alcohol metabolism results in DNA repair infidelity and cell cycle-induced senescence in neurons.

Chronic binge-like drinking is a risk factor for age-related dementia, however, the lasting and irreversible effect of alcohol on the brain remains elusive. Transcriptomic changes in brain cortices revealed pro-ageing hallmarks upon chronic ethanol exposure and these changes predominantly occur in neurons. The changes are attributed to a prioritized ethyl alcohol oxidation in these cells via the NADPH-dependent cytochrome pathway. This hijacks the folate metabolism of the 1-carbon network which supports the pathway choice of DNA repair via the non-cell cycle-dependent mismatch repair networks. The lost-in-function of such results in the de-inactivation of the less preferred cell cycle-dependent homologous recombination (HR) repair, forcing these post-mitotic cells to re-engage in a cell cycle-like process. However, mature neurons are post-mitotic. Therefore, instead of successfully completing a full round of cell cycle which is necessary for the completion of HR-mediated repair; these cells are arrested at checkpoints. The resulting persistence of repair intermediates induces and promotes the nuclear accumulation of p21 and cyclin B-a trigger for permanent cell cycle exits and irreversible senescence response. Supplementation of bioactive 5-methyl tetrahydrofolate simultaneously at times with ethyl alcohol exposure supports the fidelity of the 1-carbon network and hence the activity of the mismatch repair. This prevents aberrant and irreversible cell cycle re-entry and senescence events of neurons. Together, our findings offer a direct connection between binge-drinking behaviour and its irreversible impact on the brain, which makes it a potential risk factor for dementia.

Development of the high angular resolution 360° LiDAR based on scanning MEMS mirror.

Light detection and ranging (LiDAR) using various operational principles has been applied in many fields, e.g., robotics navigation, autonomous vehicles, unmanned aerial flyers, land surveying, etc. The multichannel LiDAR system is of great importance in the field of autonomous driving due to its larger field of view (FoV). However, the number of transceivers limits the vertical angular resolution of multichannel LiDAR systems and makes them costly. On the other hand, the emergence of microelectromechanical systems (MEMS) mirrors may provide a highly promising solution to a low-cost, high angular resolution LiDAR system. We have demonstrated a MEMS mirror-based 360° LiDAR system with high angular resolution and will present the detailed design process and obtained experimental results in this paper. With the combination of the MEMS mirror and a rotation platform for the LiDAR system, a 360° × 8.6° (horizontal × vertical) FoV was achieved. Compared with existing commercial multichannel 360° LiDAR systems, our system has 13.8 times better angular resolution than the Velodyne HDL-64 LiDAR sensor. The experimental results verified an excellent performance of 0.07° × 0.027° (horizontal × vertical) angular resolution, which enhances the panoramic scanning and imaging capability of the LiDAR system, potentially providing more accurate 3D scanning applications in areas such as autonomous vehicles, indoor surveying, indoor robotics navigation, etc.

Development of Fluorescent Turn-On Probes for CAG-RNA Repeats.

Fluorescent sensing of nucleic acids is a highly sensitive and efficient bioanalytical method for their study in cellular processes, detection and diagnosis in related diseases. However, the design of small molecule fluorescent probes for the selective binding and detection of RNA of a specific sequence is very challenging because of their diverse, dynamic, and flexible structures. By modifying a bis(amidinium)-based small molecular binder that is known to selectively target RNA with CAG repeats using an environment-sensitive fluorophore, a turn-on fluorescent probe featuring aggregation-induced emission (AIE) is successfully developed in this proof-of-concept study. The probe (DB-TPE) exhibits a strong, 19-fold fluorescence enhancement upon binding to a short CAG RNA, and the binding and fluorescence response was found to be specific to the overall RNA secondary structure with A·A mismatches. These promising analytical performances suggest that the probe could be applied in pathological studies, disease progression monitoring, as well as diagnosis of related neurodegenerative diseases due to expanded CAG RNA repeats.

Mapping of Spatiotemporal Auricular Electrophysiological Signals Reveals Human Biometric Clusters.

Underneath the ear skin there are rich vascular network and sensory nerve branches. Hence, the 3D mapping of auricular electrophysiological signals can provide new biomedical perspectives. However, it is still extremely challenging for current sensing techniques to cover the entire ultra-curved auricle. Here, a 3D graphene-based ear-conformable sensing device with embedded and distributed 3D electrodes for full-auricle physiological monitoring is reported. As a proof-of-concept, spatiotemporal auricular electrical skin resistance (AESR) mapping is demonstrated for the first time, and human subject-specific AESR distributions are observed. From the data of more than 30 ears (both right and left ears), the auricular region-specific AESR changes after cycling exercise are observed in 98% of the tests and are clustered into four groups via machine learning-based data analyses. Correlations of AESR with heart rate and blood pressure are also studied. This 3D electronic platform and AESR-based biometrical findings show promising biomedical applications.

Multifaceted investigation underlies diverse mechanisms contributing to the downregulation of Hedgehog pathway-associated genes INTU and IFT88 in lung adenocarcinoma and uterine corpus endometrial carcinoma.

Hedgehog (Hh) signaling primarily functions in the control of mammalian embryonic development but also has roles in cancer. The Hh activation depends on ciliogenesis, a cellular process that describes outgrowth of the primary cilium from cell membrane. Ciliogenesis initiation requires a set of proteins known as planar cell polarity (PCP) effectors. Inturned (INTU) is a PCP effector that reportedly functions synergistically with Hh signaling in basal cell carcinoma, suggesting that INTU has an oncogenic role. In this study, we carried out a pan-cancer investigation on the prognostic significance of INTU in different types of cancer. We demonstrated that INTU downregulation correlated with reduced survival probabilities in lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC) patients. Similar expression patterns and prognostic values were identified for intraflagellar transport 88 (IFT88), another Hh pathway-associated gene. We elucidated multiple mechanisms at transcriptional, post-transcriptional and translational levels that involved transcription factor 4 and non-coding RNAs-associated regulatory networks contributing to the reduction of INTU and IFT88 levels in LUAD and UCEC samples. Taken together, this study demonstrates the prognostic significance of the Hh-related genes INTU and IFT88 in LUAD and UCEC and further delineates multifaceted mechanisms leading to INTU and IFT88 downregulation in tumor samples.

Wide-Bandwidth Nanocomposite-Sensor Integrated Smart Mask for Tracking Multiphase Respiratory Activities.

Wearing masks has been a recommended protective measure due to the risks of coronavirus disease 2019 (COVID-19) even in its coming endemic phase. Therefore, deploying a "smart mask" to monitor human physiological signals is highly beneficial for personal and public health. This work presents a smart mask integrating an ultrathin nanocomposite sponge structure-based soundwave sensor (≈400 µm), which allows the high sensitivity in a wide-bandwidth dynamic pressure range, i.e., capable of detecting various respiratory sounds of breathing, speaking, and coughing. Thirty-one subjects test the smart mask in recording their respiratory activities. Machine/deep learning methods, i.e., support vector machine and convolutional neural networks, are used to recognize these activities, which show average macro-recalls of ≈95% in both individual and generalized models. With rich high-frequency (≈4000 Hz) information recorded, the two-/tri-phase coughs can be mapped while speaking words can be identified, demonstrating that the smart mask can be applicable as a daily wearable Internet of Things (IoT) device for respiratory disease identification, voice interaction tool, etc. in the future. This work bridges the technological gap between ultra-lightweight but high-frequency response sensor material fabrication, signal transduction and processing, and machining/deep learning to demonstrate a wearable device for potential applications in continual health monitoring in daily life.

Lignin-carbohydrate complexes suppress SCA3 neurodegeneration via upregulating proteasomal activities.

Lignin-carbohydrate complexes (LCCs) represent a group of macromolecules with diverse biological functions such as antioxidative properties. Polyglutamine (polyQ) diseases such as spinocerebellar ataxia type 3 (SCA3) comprise a set of neurodegenerative disorders characterized by the formation of polyQ protein aggregates in patient neurons. LCCs have been reported to prevent such protein aggregation. In this study, we identified a potential mechanism underlying the above anti-protein aggregation activity. We isolated and characterized multiple LCC fractions from bamboo and poplar and found that lignin-rich LCCs (BM-LCC-AcOH and PR-LCC-AcOH) effectively eliminated both monomeric and aggregated mutant ataxin-3 (ATXN3polyQ) proteins in neuronal cells and a Drosophila melanogaster SCA3 disease model. In addition, treatment with BM-LCC-AcOH or PR-LCC-AcOH rescued photoreceptor degeneration in vivo. At the mechanistic level, we demonstrated that BM-LCC-AcOH and PR-LCC-AcOH upregulated proteasomal activity. When proteasomal function was impaired, the ability of the LCCs to suppress ATXN3polyQ aggregation was abolished. Thus, we identified a previously undescribed proteasome-inducing function of LCCs and showed that such activity is indispensable for the beneficial effects of LCCs on SCA3 neurotoxicity.

A peptide inhibitor that rescues polyglutamine-induced synaptic defects and cell death through suppressing RNA and protein toxicities.

Polyglutamine (polyQ) diseases, including spinocerebellar ataxias and Huntington's disease, are progressive neurodegenerative disorders caused by CAG triplet-repeat expansion in the coding regions of disease-associated genes. In this study, we found that neurotoxic small CAG (sCAG) RNA species, microscopic Ataxin-2 CAG RNA foci, and protein aggregates exist as independent entities in cells. Synaptic defects and neurite outgrowth abnormalities were observed in mutant Ataxin-2-expressing mouse primary cortical neurons. We examined the suppression effects of the CAG RNA-binding peptide beta-structured inhibitor for neurodegenerative diseases (BIND) in mutant Ataxin-2-expressing mouse primary cortical neurons and found that both impaired synaptic phenotypes and neurite outgrowth defects were rescued. We further demonstrated that BIND rescued cell death through inhibiting sCAG RNA production, Ataxin-2 CAG RNA foci formation, and mutant Ataxin-2 protein translation. Interestingly, when the expanded CAG repeats in the mutant Ataxin-2 transcript was interrupted with the alternative glutamine codon CAA, BIND's inhibitory effect on mutant protein aggregation was lost. We previously demonstrated that BIND interacts physically and directly with expanded CAG RNA sequences. Our data provide evidence that the BIND peptide associates with transcribed mutant CAG RNA to inhibit the formation of toxic species, including sCAG RNA, RNA foci, and polyQ protein translation and aggregation.

Molecular insights into the interaction of CAG trinucleotide RNA repeats with nucleolin and its implication in polyglutamine diseases.

Polyglutamine (polyQ) diseases are a type of inherited neurodegenerative disorders caused by cytosine-adenine-guanine (CAG) trinucleotide expansion within the coding region of the disease-associated genes. We previously demonstrated that a pathogenic interaction between expanded CAG RNA and the nucleolin (NCL) protein triggers the nucleolar stress and neuronal cell death in polyQ diseases. However, mechanisms behind the molecular interaction remain unknown. Here, we report a 1.45 Å crystal structure of the r(CAG)5 oligo that comprises a full A'-form helical turn with widened grooves. Based on this structure, we simulated a model of r(CAG)5 RNA complexed with the RNA recognition motif 2 (RRM2) of NCL and identified NCL residues that are critical for its binding to CAG RNA. Combined with in vitro and in vivo site-directed mutagenesis studies, our model reveals that CAG RNA binds to NCL sites that are not important for other cellular functions like gene expression and rRNA synthesis regulation, indicating that toxic CAG RNA interferes with NCL functions by sequestering it. Accordingly, an NCL mutant that is aberrant in CAG RNA-binding could rescue RNA-induced cytotoxicity effectively. Taken together, our study provides new molecular insights into the pathogenic mechanism of polyQ diseases mediated by NCL-CAG RNA interaction.

NMR solution structures of d(GGCCTG)n repeats associated with spinocerebellar ataxia type 36.

Expansion of d(GGCCTG)n hexanucleotide repeats in the NOP56 gene is the genetic cause of spinocerebellar ataxia type 36 (SCA36) which is an inheritable neurodegenerative disease. Non-B DNA is known to be the structural intermediate causing repeat expansions. Yet, the structure and mechanism of genetic instability of d(GGCCTG)n repeats remain elusive. In this work, we investigated the solution structures of sequences containing two to eight GGCCTG repeats using nuclear magnetic resonance (NMR) spectroscopy. They were found to form diverse secondary structures, including hairpin, duplex and G-quadruplex (G4). Intriguingly, the hairpin structure was present in all the investigated sequences. The NMR solution structure of the hairpin formed by d(GGCCTG)2 was determined, disclosing an unprecedented CCTGGG hexanucleotide loop in which the first and sixth loop residues formed a Watson-Crick loop-closing base pair, the second and third loop residues stacked in the major groove, whereas the fourth and fifth loop residues formed a G·G mismatch. Apart from the hairpin, antiparallel G4 and palindromic duplex structures were found to form in d(GGCCTG)2 and d(GGCCTG)3-8, respectively. Results of this work provide new insights into the genetic instability of d(GGCCTG)n repeats and structure-based drug design for SCA36.

Interpretable Sub-phenotype Identification in Acute Kidney Injury.

Acute kidney injury (AKI) is a life-threatening and heterogeneous syndrome. Timely and etiology-based personalized treatment is crucial. AKI sub-phenotyping can lead to better understanding of the pathophysiology of AKI and help developing more targeted intervention. Current dimensionality reduction and similarity-based clustering for AKI sub-phenotyping suffer from limited interpretability and specificity. To address these limitations, we propose a pattern mining approach with multiobjective evolutionary algorithm (MOEA) for AKI sub-phenotyping. AKI sub-phenotypes are presented as explicit rules, so no post-hoc explanation is needed. Also, our method can search feature subspace efficiently for minor and highly specific sub-phenotypes. We aimed to discover sub-phenotypes for AKI patients against non-AKI patients (AKI vs non-AKI) and moderate-to-severe AKI patients against mild AKI patients (AKI-2/3 vs AKI-1). We identified 174(178) significant sub-phenotypes with average confidence of 0.33(0.33). Our method can assign patients to a sub-phenotype with higher confidence than k-means clustering, with average improvement of 0.20(0.23).

Rapid nanomolding of nanotopography on flexible substrates to control muscle cell growth with enhanced maturation.

In vivo, multiple biophysical cues provided by highly ordered connective tissues of the extracellular matrix regulate skeletal muscle cells to align in parallel with one another. However, in routine in vitro cell culture environments, these key factors are often missing, which leads to changes in cell behavior. Here, we present a simple strategy for using optical media discs with nanogrooves and other polymer-based substrates nanomolded from the discs to directly culture muscle cells to study their response to the effect of biophysical cues such as nanotopography and substrate stiffness. We extend the range of study of biophysical cues for myoblasts by showing that they can sense ripple sizes as small as a 100 nm width and a 20 nm depth for myotube alignment, which has not been reported previously. The results revealed that nanotopography and substrate stiffness regulated myoblast proliferation and morphology independently, with nanotopographical cues showing a higher effect. These biophysical cues also worked synergistically, and their individual effects on cells were additive; i.e., by comparing cells grown on different polymer-based substrates (with and without nanogrooves), the cell proliferation rate could be reduced by as much as ~29%, and the elongation rate could be increased as much as ~116%. Moreover, during myogenesis, muscle cells actively responded to nanotopography and consistently showed increases in fusion and maturation indices of ~28% and ~21%, respectively. Finally, under electrical stimulation, the contraction amplitude of well-aligned myotubes was found to be almost 3 times greater than that for the cells on a smooth surface, regardless of the substrate stiffness.

CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration.

DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington's disease (HD). In this study, we showed that the expression of untranslatable expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the Nudix hydrolase 16 (NUDT16) gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing NUDT16 mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of NUDT16 and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent NUDT16 silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases.

COVID-19, community response, public policy, and travel patterns: A tale of Hong Kong.

The COVID-19 outbreak has necessitated a critical review of urban transportation and its role in society against the backdrop of an exogenous shock. This article extends the transportation literature regarding community responses to the COVID-19 pandemic and what lessons can be obtained from the case of Hong Kong in 2020. Individual behavior and collective responsibility are considered crucial to ensure both personal and community wellbeing in a pandemic context. Trends in government policies, the number of infectious cases, and community mobility are examined using multiple data sources. The mobility changes that occurred during the state of emergency are revealed by a time-series analysis of variables that measure both the epidemiological severity level and government stringency. The results demonstrate a high response capability of the local government, inhabitants, and communities. Communities in Hong Kong are found to have reacted faster than the implementation of health interventions, whereas the government policies effectively reduced the number of infection cases. The ways in which community action are vital to empower flexible and adaptive community responses are also explored. The results indicate that voluntary community involvement constitutes a necessary condition to help inform and reshape future transport policy and response strategies to mitigate the pandemic.

Pan-cancer investigation reveals mechanistic insights of planar cell polarity gene Fuz in carcinogenesis.

The fuzzy planar cell polarity protein (Fuz) is an effector component of the planar cell polarity (PCP) signaling. Together with other core and effector proteins, the PCP pathway controls polarized cell movements. Fuz was also reported as a negative regulator of cell survival. In this study, we performed a pan-cancer survey to demonstrate the role of Fuz in multiple types of cancer. In head-neck squamous cell carcinoma and lung adenocarcinoma tumor samples, a reduction of Fuz transcript expression was detected. This coincides with the poor overall survival probabilities of these patients. We further showed that Fuz promoter hypermethylation contributes to its transcriptional downregulation. Meanwhile, we also identified a relatively higher mutation frequency at the 404th arginine amino acid residue in the coding sequence of Fuz locus, and further demonstrated that mutant Fuz proteins perturb the pro-apoptotic function of Fuz. In summary, our study unveiled an intriguing relationship between Fuz dysregulation and cancer prognosis, and further provides mechanistic insights of Fuz's involvement in carcinogenesis.

A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3.

Polyglutamine (polyQ) diseases comprise Huntington's disease and several subtypes of spinocerebellar ataxia, including spinocerebellar ataxia type 3 (SCA3). The genomic expansion of coding CAG trinucleotide sequence in disease genes leads to the production and accumulation of misfolded polyQ domain-containing disease proteins, which cause cellular dysfunction and neuronal death. As one of the principal cellular protein clearance pathways, the activity of the ubiquitin-proteasome system (UPS) is tightly regulated to ensure efficient clearance of damaged and toxic proteins. Emerging evidence demonstrates that UPS plays a crucial role in the pathogenesis of polyQ diseases. Ubiquitin (Ub) E3 ligases catalyze the transfer of a Ub tag to label proteins destined for proteasomal clearance. In this study, we identified an E3 ligase, pre-mRNA processing factor 19 (Prpf19/prp19), that modulates expanded ataxin-3 (ATXN3-polyQ), disease protein of SCA3, induced neurodegeneration in both mammalian and Drosophila disease models. We further showed that Prpf19/prp19 promotes poly-ubiquitination and degradation of mutant ATXN3-polyQ protein. Our data further demonstrated the nuclear localization of Prpf19/prp19 is essential for eliciting its modulatory function towards toxic ATXN3-polyQ protein. Intriguingly, we found that exocyst complex component 7 (Exoc7/exo70), a Prpf19/prp19 interacting partner, modulates expanded ATXN3-polyQ protein levels and toxicity in an opposite manner to Prpf19/prp19. Our data suggest that Exoc7/exo70 exerts its ATXN3-polyQ-modifying effect through regulating the E3 ligase function of Prpf19/prp19. In summary, this study allows us to better define the mechanistic role of Exoc7/exo70-regulated Prpf19/prp19-associated protein ubiquitination pathway in SCA3 pathogenesis.