It is well acknowledged that metabolic disorder binds closely with preeclampsia, though some of the causal relationships are still ambiguous. This review systematically summarizes the metabolic characteristics of carbohydrates, lipids, amino acids, and glycans in preeclampsia, highlighting their roles in oxidative stress, trophoblast autophagy, inflammatory response, and vascular tone regulation. Key findings include upregulated glycolysis and impaired mitochondrial function contributing to ATP deficiency, dysregulated lipid metabolism exacerbating oxidative stress and vascular dysfunction, and amino acid imbalances disrupting immune responses and redox homeostasis. Emerging therapies, such as metformin and pravastatin, demonstrate potential in targeting these pathways for prevention and treatment. Here, we reviewed thoroughly the related literature with a view to delineating the potential association of nutrient metabolism with preeclampsia, so that we could explore a promising therapeutic approach.

Fetal growth restriction (FGR) is a major determinant of perinatal morbidity and mortality. Our study aimed to develop a prediction model for the risk of FGR developing adverse perinatal outcome (APO) and evaluate its performance. This was a prospective observational cohort study of consecutive singleton gestations meeting the ACOG-endorsed criteria for FGR from January 2022 to June 2023 at Obstetrics and Gynecology Hospital of Fudan University. Clinical information, ultrasound indicators and serum biomarkers were collected. The primary composite APO comprised one or more of: perinatal death, intrauterine demise, intraventricular hemorrhage, periventricular leukomalacia, seizures, necrotizing enterocolitis, neonatal respiratory distress syndrome, sepsis and the length of stay in the neonatal intensive care unit > 7 days. Least absolute shrinkage and selection operator regression was used to screen variables for nomogram model construction. The discrimination, calibration and clinical effectiveness of the nomogram were evaluated using receiver operating characteristic curve, calibration plots and decision curve analysis in training and validation cohorts. A total of 122 pregnancies were enrolled in the final statistical analysis. Five variables were identified to establish a nomogram, including gestational weeks at diagnosis, abnormal umbilical artery Doppler, abnormal uterine artery Doppler, and multiples of the median values of placental growth factor and soluble fms-like tyrosine kinase-1. The area under the receiver-operating-characteristics curve of 0.87 (95

Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation. Identifying molecular glues is challenging. There is a scarcity of target-specific upregulating molecular glues, which are highly anticipated for numerous targets, including P53. P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases, whereas deubiquitinases (DUBs) remove polyubiquitination conjugates to counteract these E3 ligases. Thus, small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination. Here, using small-molecule microarray-based technology and unbiased screening, we identified three potential molecular glues that may tether P53 to the DUB, USP7, and elevate the P53 level. Among the molecular glues, bromocriptine (BC) is an FDA-approved drug with the most robust effects. BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7.Consistent with P53 upregulation in cancer cells, BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model. In summary, we established a potential screening platform and identified potential molecular glues upregulating P53. Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.

Importance Antenatal corticosteroid treatment of individuals with singletons at risk for delivery during the late-preterm period has been academically recommended. However, the evidence on the use of antenatal corticosteroid treatment for twins at risk for delivery during the late-preterm period is still lacking.Objective To evaluate whether antenatal corticosteroid treatment during the late-preterm period in twin pregnancies was associated with a lower risk of newborn morbidity.Design, Setting, and Participants This retrospective cohort study of twin pregnancies delivered from February 1, 2013, to September 30, 2020, in a university-affiliated hospital in China included 1974 individuals with twin pregnancies who were at risk for late preterm birth (34 weeks and 0 days to 36 weeks and 6 days of gestation). Data were analyzed from June 30 to July 13, 2023.Exposures Antenatal corticosteroid treatment during the late-preterm period.Main Outcomes and Measures The primary outcome measure was composite neonatal respiratory morbidity, defined as at least 1 of the following postnatal occurrences in at least 1 neonate of the twins: respiratory distress syndrome, mechanical ventilation, surfactant administration, transferred with respiratory complications, or neonatal death. Propensity score overlap weighting was used to analyze the association between antenatal corticosteroid treatment and the risk of neonatal outcomes.Results The study population consisted of 1974 individuals with twin pregnancies, including 303 (15.3%; mean [SD] maternal age, 30.8 [4.2] years) who received antenatal corticosteroid treatment and 1671 (84.7%; mean [SD] maternal age, 31.2 [4.0] years) who did not receive antenatal corticosteroid treatment. The propensity score overlap weighting showed no significant differences between the antenatal corticosteroid treatment group and the no-antenatal corticosteroid treatment group in the risk of neonatal primary outcome (29 of 303 [9.6%] vs 41 of 1671 [2.5%]; weighted odds ratio, 1.27 [95% CI, 0.60-2.76]). None of the subgroup interaction tests were significant for the neonatal primary outcome in terms of gestational age at delivery, year of delivery, chorionicity, at least 1 infant small for gestational age, intertwin growth discordance, and infant sex, and neither was the sensitivity analysis of using propensity score matching and a different administration-to-birth interval and treating twin infants as individuals.Conclusions and Relevance This cohort study found insufficient evidence that antenatal corticosteroid treatment during the late-preterm period in twin pregnancies could be associated with a lower risk of newborn morbidity. This new finding can provide a reference for clinical practice.

Background Preeclampsia is a common pregnancy complication characterized by high blood pressure and damage to organs. Abnormal placenta and vascular function can lead to preeclampsia. Accumulating evidence has suggested a potential link between circular RNAs (circRNAs) and preeclampsia. As a placenta and endothelial-expressed circRNA, hsa_circ_0002348, may be promising to be the novel molecular target for preeclampsia. However, the function and mechanism of hsa_circ_0002348 in preeclampsia has not been elucidated. Materials and methods An overlap analysis of two circRNA profiles from placenta and endothelial cells was used to identify a functionally unknown circRNA, hsa_circ_0002348. Quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH) were used to detect its expression in the trophoblast cells and placental tissues. The mouse model of lipopolysaccharide (LPS)-induced preeclampsia was established to determine the in vivo role of hsa_circ_0002348. RNA immunoprecipitation (RIP), Luciferase reporter assay, qRT-PCR, western blot, gain- and loss-of-function and rescue experiments were conducted to uncover the role of hsa_circ_0002348 and its interaction with miR-126-3p and BAK1 in regulating trophoblast proliferation and apoptosis. Fluorescence in situ hybridization (FISH) and Immunohistochemistry (IHC) were performed to examine the expression of miR-126-3p and BAK1 in mice and human placentas, respectively. Results Hsa_circ_0002348 was significantly increased in the preeclampsia placentas, and positively correlated with the severity of preeclampsia patients’ clinical manifestations. Its overexpression exacerbated preeclampsia-like features in the mouse model of LPS-induced preeclampsia. Functionally, hsa_circ_0002348 was found to inhibit trophoblast proliferation and promote trophoblast apoptosis. Mechanistically, hsa_circ_0002348, as an endogenous miR-126-3p sponge, upregulated the expression of BAK1. Additionally, both hsa_circ_0002348 knockdown and miR-126-3p overexpression enhanced the mammalian target of rapamycin (mTOR) and ERK1/2 signaling pathway. Conclusions Hsa_circ_0002348 might be a novel regulator of trophoblast proliferation and apoptosis through miR-126-3p/BAK1 axis in preeclampsia, which may serve as a potential target for detecting and treating preeclampsia.

Parkinson’s disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases, including inflammatory bowel disease and neurodegenerative diseases; however, its precise role in PD remains unclear. Here, we investigated the neuroprotective role of MLKL inhibition or ablation against primary neuronal cells and human iPSC-derived midbrain organoids induced by toxic α-Synuclein preformed fibrils (PFFs). Using a mouse model (Tg-Mlkl−/−) generated by crossbreeding the SNCA A53T synuclein transgenic mice with MLKL knockout (KO)mice, we assessed the impact of MLKL deficiency on the progression of Parkinsonian traits. Our findings demonstrate that Tg-Mlkl−/− mice exhibited a significant improvement in motor symptoms and reduced phosphorylated α-synuclein expression compared to the classic A53T transgenic mice. Furthermore, MLKL deficiency alleviated tyrosine hydroxylase (TH)-positive neuron loss and attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Single-cell RNA-seq (scRNA-seq) analysis of the SN of Tg-Mlkl−/− mice revealed a unique cell type-specific transcriptome profile, including downregulated prostaglandin D synthase (PTGDS) expression, indicating reduced microglial cells and dampened neuron death. Thus, MLKL represents a critical therapeutic target for reducing neuroinflammation and preventing motor deficits in PD.

Objective To explore the optimal cutoffs of growth discordance for the risk of preeclampsia in twin pregnancies. Methods A retrospective cohort study in a university hospital which included twins delivered from February 2013 to September 2020. Restrictive cubic spline (RCS) model was applied to the trend of intertwin birthweight difference (BWD) with the risk of preeclampsia. Logistic regression and subgroup analysis were performed to find the cut-off with statistical significance and clinical meaningfulness. Results A total of 2,631 women pregnant with twins were enrolled. RCS showed a nonlinear upward trend of preeclampsia with BWD, and the BWD of 15% was the initial rising point. With the confounders adjusted, only the group with BWD ≥ 25% was found to be significantly associated with an increased risk of preeclampsia (adjusted odds ratio [aOR], 2.44; 95% confidence interval [CI]: 1.74–3.42). Additionally, subgroup analysis showed that both monochorionic (MC) and small for gestational age (SGA) twins were more likely to complicate with preeclampsia. Conclusion The growth discordance of 15% during pregnancy may be the preventive point of preeclampsia, and 25% may be the interventional point.

To the Editor: Preeclampsia presents with new-onset hypertension and maternal multi-organ injury that is associated with substantial maternal and fetal morbidity and mortality.[1] Although the etiology remains a mystery, environmental toxicants, especially those that interact with genetic factors and disrupt normal placental function, are emerging as potential risk factors for preeclampsia. Perfluoroalkyl and polyfluoroalkyl substances (PFAS), a kind of aliphatic chemicals, have been widely used in industries and consumer products for their excellent properties of heat-, water- and oil-resistance, leading to ubiquitous contamination and inevitable human exposure. The long-chain perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), as the most widely used representatives, have been detected in the blood, human cord blood, and breast milk of the general population.[2] Previously, several epidemiological studies have examined the associations between PFOS/PFOA and preeclampsia, but have found inconsistent results, which may reflect differences in outcome assessments, analysis methods, and/or study population.[3] Since the 3M Company, one of the largest PFAS manufacturers, phased out PFOS and PFOA production from 2002, PFOS and PFOA production volumes have been increasing in China. However, the risk of preeclampsia with PFOS and PFOA exposure is much rarely described in China, especially in the most intensively industrialized regions, such as the eastern coast. Thus, we explore the association between maternal serum concentrations of PFOS and PFOA and the risk of developing preeclampsia in Shanghai, China. A nested case–control study was conducted in a longitudinal cohort of pregnant women enrolled in the year 2016 at the Obstetrics and Gynecology Hospital of Fudan University. Eligible subjects were women with singleton pregnancies who were later delivered in the study hospital. Those with complications including diabetes mellitus, fetal malformation, chronic hypertension, kidney disease, or any additional vital pre-existing chronic disorders were excluded. The diagnosis of preeclampsia was based on the 2013 American College of Obstetricians and Gynecologists (ACOG) guidelines. Maternal serum samples of 5 mL were collected into vacuum polypropylene tubes without additives at 16 to 20 gestational weeks (the time of Down's screening). Immediately, the serum samples were sent blindly on dry ice to the laboratories. Serum PFOS and PFOA concentrations were evaluated by high-performance liquid chromatography–mass spectrometry. The limit of detection (LOD) for PFOS and PFOA was 0.1 ng/mL. We substituted the value by dividing the LOD (0.1 ng/mL) by two if the concentration was less than the LOD. The epidemiological and clinical data were extracted from the electronic medical records. Our protocol was approved by the Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University, and each subject signed informed consent. Statistical analyses were carried out using IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp, NY, USA). The general characteristics of the participants were calculated and reported as mean ± standard deviation for continuous variables and n (%) for categorical variables. The differences between groups were analyzed by the Student's t test for normally distributed continuous variables and by the Mann–Whitney U test for non-normally distributed continuous variables. The chi-squared test was used for categorical variables. Multiple logistic regression analysis was conducted to explore the preeclampsia risk for PFOS and PFOA levels by calculating odds ratios (ORs) and 95% confidence intervals (95% CIs). Furthermore, we used restricted cubic splines with three knots at the 10th, 50th, and 90th percentiles of the PFOS and PFOA concentrations, with the reference value (OR = 1) set at the 50th percentile. The results were adjusted for potential confounders including maternal age, parity, and body mass index (BMI), which have been reported to be associated with preeclampsia. P value <0.05 represented statistical significance. A total of 4716 pregnant women were enrolled. 1147 women were excluded due to gestational or pregestational diabetes mellitus (N = 849), fetal malformation (N = 76), chronic hypertension (N = 54), kidney disease (N = 27), or any additional vital pre-existing chronic disorders (N = 141). After exclusion, 3569 participants remained, among whom 88 developed preeclampsia. Controls (n = 88) were selected from healthy full-term pregnant women of similar ages and blood collection dates. Two samples of preeclampsia cases were missed and therefore removed for additional analysis [Supplementary Figure 1, https://links.lww.com/CM9/B220]. There were no statistically significant differences between the groups regarding maternal age, educational level, parity, and sampling time. Participants in the preeclampsia group had a higher BMI at the first visit, which was corrected in subsequent regression analysis. In addition, compared with the results of the controls, cases had earlier gestational delivery weeks and a higher proportion of cesarean section. However, these two factors were outcome indicators and had a negligible impact on our analysis. No participants consumed alcohol or smoked cigarettes [Supplementary Table 1, https://links.lww.com/CM9/B220]. Only two samples (1.2%) in the control group had lower concentrations of PFOS than LOD (<0.1 ng/mL). The median (25th, 75th) concentrations in all subjects were 7.1 ng/mL (3.9–23.5 ng/mL) for PFOS and 17.6 ng/mL (13.3–25.7 ng/mL) for PFOA. The preeclampsia cases had higher PFOS and PFOA concentrations than controls. In subgroup analysis, all subsets of preeclampsia had significantly increased serum PFOS concentrations compared to controls (all P values <0.001). Significantly higher PFOA concentrations were observed in severe and late-onset preeclampsia compared with controls (P < 0.05). Among pre-eclampsia subjects, significantly higher PFOS concentrations were observed in mild-pre-eclampsia cases compared with severe-pre-eclampsia cases (P < 0.001) [Table 1]. Table 1 - Maternal serum PFOS and PFOA concentrations in the study population. Population Group N PFOS concentrations (ng/mL) P value∗ P value† PFOA concentrations (ng/mL) P-value∗ P-value† Controls 88 4.6 (3.6, 7.1) Ref / 16.1 (13.2–21.4) Ref / Preeclampsia 86 23.3 (7.7, 34.3) <0.001 / 19.3 (14.3–27.0) 0.012 / Severity Mild 53 18.3 (4.4, 29.9) <0.001 Ref 18.0 (11.3–26.4) 0.127 Ref Severe 33 29.2 (19.8, 48.4) <0.001 <0.001 23.0 (16.4–31.1) 0.002 0.065 Onset time Early 15 23.4 (15.7, 32.2) <0.001 Ref 19.1 (16.2–30.0) 0.095 Ref Late 71 23.3 (7.2, 35.3) <0.001 0.277 20.1 (12.5–26.9) 0.017 0.165 Data are presented as n or median (25th, 75th).∗Preeclampsia and the subsets were separately compared with controls.†Comparisons were conducted among subsets.PFOA: Perfluorooctanoate; PFOS: Perfluorooctane sulfonate; Ref: Reference. In the logistic regression models, the estimated ORs (95% CI) of preeclampsia risk significantly increased 7.7-fold (3.8–15.7) compared with low PFOS concentrations after adjusting for maternal age, BMI, and parity when the median value of 7.1 ng/mL was selected as the point of interception. On the other hand, higher PFOA exposure increased 1.8-fold the risk of preeclampsia after adjusting for potential confounders, although it was not significant [Supplementary Table 2, https://links.lww.com/CM9/B220]. Restricted cubic splines showed significant linear dose-response relationships between PFOS and the risk of preeclampsia. The association between PFOA and preeclampsia was not statistically significant [Supplementary Figure 2, https://links.lww.com/CM9/B220]. In our nested case–control study, we found that the maternal serum concentrations of PFOS were significantly positively associated with higher odds of preeclampsia, while the association of PFOA was mild. These findings provided new targets for the etiological prevention of preeclampsia and put forward a basis for the formulation of public health policy. Studies of highly exposed communities in the US-based C8 Health Project reported PFOS and PFOA had modestly associated with maternally self-reported preeclampsia.[4] However, there were certain inherent limitations in these data, mainly including exposure measurement bias on PFOS and PFOA contaminated drinking water and information error caused by the self-reporting outcomes, so the results may not be generalizable to other populations. In a Norwegian MoBa cohort, increased levels of PFOS had minor associations with preeclampsia risk in nulliparous women at mid-pregnancy (around 17–20 gestational weeks).[5] However, preeclampsia diagnosis was obtained from registers. Likewise, another Chinese study found no association between cord blood PFOS and PFOA concentrations and preeclampsia, while cord blood may not be a good biomarker for early pregnancy exposure.[6] To overcome these shortcomings, our study was performed on the general population and maternal blood samples were used to determine PFOS and PFOA levels, which is believed to be a better biomarker to reflect internal exposure in pregnant women. Besides, the serum collection time was chosen at the first half of pregnancy (16–20 gestational weeks) in order to coincide with the window of spiral arteries remodeling and placental development. In addition, the nested case–control design enabled us to select all preeclampsia cases and matched control subjects to avoid selection bias. These data provide further evidence of a causal relationship between PFOS and PFOA exposure and preeclampsia. Our study showed that almost all pregnant women in Shanghai are widely exposed to PFOS and PFOA. With the use of PFOS and PFOA being restricted by the government in the United States in 2001 and Europe in 2008, more chemical industries have shifted and relocated from Europe and America to Asia. Actually, the annual production of PFOS and PFOA has skyrocketed since 2003 in China due to increasing demand in both domestic and overseas markets. Thus, we will be more likely to be exposed to PFOS and PFOA in the future. The PFOS and PFOA concentrations in our study were almost at the same level as those obtained in the Shanghai Birth Cohort Study conducted at Xinhua Hospital between 2013 and 2015 (PFOS 8.2 ng/mL; PFOA 11.6 ng/mL).[7] Consequently, stronger and harsher monitoring should be adopted to control PFOS and PFOA pollution for the preservation of human health. Several limitations should be mentioned in this study. First, the firm causal relationship cannot be established owing to the observational design. Second, the blood samples were only obtained at a single time point of 16 to 20 gestational weeks, which may not comprehensively reflect PFAS exposure before and during pregnancy. However, considering its long half-life in the body, a single estimation may have minimal influence on the results. Third, we cannot, as with all observational studies, exclude the effect of other unmeasured factors on the results, even though we adjusted for many potential confounders. Finally, since the participants included in our study were of Han ethnicity and enrolled from only Shanghai, China, the results may not be generalizable to other racial groups or other localities. Overall, this study confirmed that pregnant women in Shanghai, China were extensively exposed to PFOS and PFOA, and that serum PFOS concentrations were closely associated with the risk of developing preeclampsia. The result supports the development of a public health policy with a view to protecting maternal and fetal health by restricting the use of PFOS and PFOA. Moreover, our study provides a base for future research on the mechanisms that will provide biological plausibility on the causality between PFAS exposure and preeclampsia. Statement All the authors have read the manuscript and approved for submission. All the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This work was supported by grants from the National Science Fund of China (81200449) and the National Science Fund of Shanghai, China (12ZR1403700). Conflicts of interest None.

Objective To investigate the relationship between mild congenital pulmonary airway malformation (CPAM) and its long-term prognosis in childhood and to explore whether surgery is necessary. Methods We conducted a retrospective cohort of fetuses with mild CPAM diagnosed prenatally with available long-term outcomes in childhood from 2004 to 2016. The patients were divided into two groups according to the fetal CPAM-to-volume ratio (CVR) of less than 1.0 and 1.0-1.6. The primary outcome was a postnatal composite outcome including CPAM-associated respiratory symptoms and surgical resection of the lesion. The secondary outcomes included neonatal asphyxia, perinatal morbidity and mortality. Results Forty-two fetuses were identified as having CVR <1.0 or CVR-1.0-1.6 respectively (n = 37 vs n = 5; 88.1% vs 11.9%), with the median duration of follow up 2.15 years (0.3-10.8 years). Of 42 patients, 32 (76%) remained asymptomatic without recurrent respiratory symptoms or surgical resection; the other 10 with CVR <1.0 had respiratory symptoms. Of 10 symptomatic cases, five recovered after expectant treatment, and five underwent resection, for an increase in lesion size and recurrent respiratory infection. Conclusion Patients with CVR <1.0 still need to be closely observed after birth. Conservative management is a reasonable option in asymptomatic cases, but surgery might be necessary in some.

Autophagy is a powerful protein degradation pathway with limited specificity. Our recent study proposed and demonstrated a potential strategy to harness autophagy to selectively degrade a specific pathogenic protein using autophagosome tethering compounds (ATTEC). ATTEC interact with both the target protein and the autophagosome protein LC3, and thus tether the target protein to the autophagosomes for subsequent degradation. The concentration-dependent curve of the target protein is U-shaped, but there has been lack of both kinetic and steady-state modeling of the degradation effects of ATTEC. Here we established a simplified model describing the kinetics and steady-state level of target protein, and characterized how compounds’ properties, especially binding affinities to LC3 and to the target protein, may influence their degradation effects.

Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders, including Huntington disease [caused by expanded CAG repeats (CAGr) in the HTT gene], and amyotrophic lateral sclerosis [ALS, possibly caused by expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene], of which the molecular mechanisms remain unclear. Here, we demonstrated that lowering the Drosophila homologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r. Expression of human tau (htau4R) restored the disease-related phenotypes that had been mitigated by the loss of dtau, suggesting an evolutionarily-conserved role of tau in neurodegeneration. We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome-lysosome fusion, possibly due to lowering the level of BAG3, a regulator of autophagy and tau. Taken together, our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism. Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.

Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders including Huntington disease (HD, caused by the expanded CAG repeats ( CAGr ) in the HTT gene) and amyotrophic lateral sclerosis (ALS, could be caused by the expanded GGGGCC repeats ( G4C2r ) in the C9ORF72 gene), of which the molecular mechanisms remain unclear. Here we demonstrate that loss of the Drosophila orthologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and shortened life-span in Drosophila models expressing mutant HTT protein with expanded CAGr or the expanded G4C2r . Importantly, expression of human tau (htau4R) restored the disease-relevant phenotypes that were mitigated by the loss of dtau, suggesting a conserved role of tau in neurodegeneration. We further discovered that G4C2r expression increased dtau accumulation, possibly due to reduced activity of BAG3-mediated autophagy. Our study reveals a conserved role of tau in G4C2r -induced neurotoxicity in Drosophila models, providing mechanistic insights and potential therapeutic targets.

See Huang and Gitler (doi:10.1093/brain/awy112) for a scientific commentary on this article. Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington's disease is an appealing disease for testing this strategy because of its monogenetic nature. Huntington's disease is mainly caused by cytotoxicity of the mutant HTT protein with an expanded polyglutamine repeat tract. Lowering the soluble mutant HTT may reduce its downstream toxicity and provide potential treatment for Huntington's disease. This is hard to achieve by small-molecule compound drugs because of a lack of effective targets. Here we demonstrate Gpr52, an orphan G protein-coupled receptor, as a potential Huntington's disease drug target. Knocking-out Gpr52 significantly reduces mutant HTT levels in the striatum and rescues Huntington's disease-associated behavioural phenotypes in a knock-in Huntington's disease mouse model expressing endogenous mutant Htt. Importantly, a novel Gpr52 antagonist E7 reduces mutant HTT levels and rescues Huntington's disease-associated phenotypes in cellular and mouse models. Our study provides an entry point for Huntington's disease drug discovery by targeting Gpr52.