Neuroscience
Abstract
Loss-of-function mutations in DNAJC6, encoding the co-chaperone auxilin (HSP40 family), cause familial juvenile-onset Parkinson’s disease (PD). Given the chaperone role of DNAJC6 in cellular homeostasis in adult neurons, we hypothesized that DNAJC6 dysfunction may not be limited to juvenile-onset disorders but could also be associated with adult-onset brain diseases. Here, we show that DNAJC6 expression is significantly downregulated in postmortem substantia nigra tissues and transcriptomic datasets from patients with late-onset sporadic PD. Consistently, human pluripotent stem cell–derived midbrain cultures exhibited reduced DNAJC6 expression under multiple PD-associated conditions. Mechanistically, DNAJC6 loss resulted from impaired transcription mediated by midbrain-specific factors NURR1/FOXA2 and reduced protein stability regulated by LRRK2. Beyond neurons, DNAJC6 was robustly expressed in astrocytes and similarly downregulated in sporadic PD contexts. Astrocytic DNAJC6 deficiency impaired phagocytic, autolysosomal, and mitochondrial functions while promoting a pro-inflammatory phenotype, thereby exacerbating neurodegenerative pathology. Importantly, epigenetic restoration of DNAJC6 in neurons and astrocytes using a CRISPRa-AAV9 system in the substantia nigra of an α-synuclein–induced PD mouse model alleviated behavioral deficits and neuropathology. These findings provide evidence that DNAJC6 dysregulation is associated with pathogenic processes in sporadic PD and suggest that targeting neuronal and astrocytic DNAJC6 could represent a potential disease-modifying strategy.
Authors
Wahyu Handoko Wibowo Darsono, Yeongran Hwang, Erica Valencia, Leonardo Tejo Gunawan, Seung Jae Hyeon, Hoon Ryu, Thor D. Stein, Mi-Yoon Chang, Noviana Wulansari, Sang-Hun Lee
Abstract
Traumatic brain injury (TBI) disproportionately affects the elderly, yet the underlying mechanisms remain unclear. Here, we demonstrate that aged TBI brains predominantly harbor pro-inflammatory NLRP3+ microglia, in stark contrast to the neuroprotective Lysozyme+ microglia prevalent in young TBI brains. This age-dependent microglial dichotomy correlates with elevated mortality and impaired recovery in aged TBI mice. By leveraging an integrative multi-omics approach combined with metabolomics and epigenome analysis, we identify a previously unrecognized link between enhanced glycolysis and pro-inflammatory chromatin landscape in NLRP3+ microglia. Further investigation identifies ELF1 as a key transcription factor driving NLRP3+ microglia formation. Importantly, ablation of ELF1 reverses age-associated microglial dysfunction and improves TBI outcomes. Finally, we discover that Imeglimin, a clinically approved antihyperglycemic agent capable of crossing the blood brain barrier, inhibits ELF1 and reverses microglial phenotype, reducing acute mortality rate and leading to improved functional recovery of aged TBI mice. Our work elucidates the mechanistic basis of age-dependent TBI outcomes, reveals the crosstalk between metabolic rewiring and epigenetic regulation in microglial aging, and identifies ELF1 as a promising therapeutic target for improving TBI outcome.
Authors
Zhichao Lu, Yi Shuai, Chenxing Wang, Zongheng Liu, Ziheng Wang, Qianqian Liu, Rui Jiang, Jue Zhu, Yongqi Zhu, Weiquan Liao, Xingjia Zhu, Jingwei Zhao, Kaibin Shi, Wei Shi, Peipei Gong
Abstract
Sleep disturbances are among the most prevalent clinical features of FOXP1 syndrome, yet their nature and underlying mechanisms remain unclear. Here, we report that individuals with FOXP1 syndrome suffer from insomnia with sleep maintenance problems and early waking. Consistently, common variants in FOXP genes were associated with insomnia symptoms and short sleep. These sleep disturbances were recapitulated in Drosophila FoxP mutants, which exhibit severely fragmented and reduced sleep. FoxP loss also led to circadian arrhythmicity and impaired the plasticity of neuropeptide pigment dispersing factor–secreting (PDF-secreting) neurons in a non-cell-autonomous manner. FoxP was required during development for adult sleep integrity, particularly in peptidergic neurons. Transcriptomic analyses revealed a dysregulation of genes involved in peptidergic signaling, including hugin. FoxP was expressed in hugin+ neurons (afferent to PDF-secreting neurons) during development, and its knockdown in these cells was sufficient to induce sleep fragmentation. Our findings establish an evolutionarily conserved role for FOXP proteins in the peptidergic regulation of sleep.
Authors
Mireia Coll-Tané, Ilse Eidhof, Jie Han, Nicholas Raun, Lara V. van Renssen, Simon E. Fisher, Matthew S. Kayser, Tjitske Kleefstra, Sigrid Pillen, Caitlin M. Hudac, Jordi Mayneris-Perxachs, Marieke Klein, Saskia Koene, Anna Castells-Nobau, Annette Schenck
Abstract
VPS13A is an intracellular lipid transfer protein comprising over 3,000 amino acids. Mutations in human VPS13A cause VPS13A disease, a neurodegenerative disorder that affects movement and cognition. VPS13A forms a complex with the membrane protein XK to mediate ATP-induced phospholipid scrambling in the plasma membrane. Here, we established a mouse cell system expressing full-length mouse VPS13A and examined its interaction with XK. Mutational analysis revealed that VPS13A binds to XK through a C-terminal β-strand that interacts with a β-hairpin in the central region of XK, an interaction essential for scramblase activity. The XK paralog XKR2, which contains a similar β-hairpin structure, also associates with VPS13A and supports phospholipid scrambling. We analyzed ten mouse VPS13A variants corresponding to patient mutations and classified them into four groups: (1) L67P, I90K, and W2453R, which showed reduced expression; (2) A1091P and M3080R, which were normally expressed but lacked scramblase activity; (3) S1446P, Q2689H, Y2713C, and R3084H, which modestly impaired expression or activity; and (4) I2763R, which altered cell size, and disrupted ER independently of XK. These findings define the VPS13A–XK interaction interface, clarify the functional impact of disease-causing mutations, and reveal an unexpected gain-of-function mutation of a VPS13A variant.
Authors
Xing Lin, Yuta Ryoden, Chigure Suzuki, Hiroyuki Ishikawa, Takaharu Sakuragi, Yasuo Uchiyama, Shigekazu Nagata
Abstract
Despite substantial progress in understanding the molecular pathology of Parkinson’s disease (PD), the underlying drivers of PD in many cases remain unknown. Here we investigate the role of RNA modification in PD, following observations of selective m6A hypomethylation in the substantia nigra (SN) of mouse PD models and dysregulated METTL3 and ALKBH5 expression in dopaminergic (DA) neurons from PD patients. We find preferential m6A deposition on transcripts of PD risk genes and a previously unreported heterozygous METTL3 p.K480R mutation in PD patients. Mettl3K480R/+ mice exhibit progressive METTL3 reduction and m6A hypomethylation in the SN, leading to progressive DA neuron loss, phospho-α-synuclein increase, and levodopa-responsive motor and non-motor deficits, mimicking PD progression. Dopamine transporter-specific METTL3 knockout mice recapitulate m6A hypomethylation, neurodegeneration and levodopa-responsive parkinsonism. Mechanistically, m6A deficiency disrupts mitochondrial biogenesis and function through regulating Tfam expression, while mitochondrial dysfunction reciprocally impairs m6A deposition, creating a pathogenic loop. Importantly, supplementation with S-adenosylmethionine (SAMe) enhances m6A modification, disrupts the pathogenic loop and alleviates parkinsonism in mouse models. Our findings reveal m6A dysregulation as an important contributor to PD pathogenesis, provide a valuable preclinical mouse model for PD progression, and highlight RNA methylation-targeted therapies as a promising strategy for PD intervention.
Authors
Sun Liu, Qihuan Ren, Guiling Mo, Zengguang Li, Huili Huang, Yuhao Zhou, Ziteng Miao, Xin Cao, Bilian Wu, Zhuoyu Xiao, Shihui Yu, Guangjin Wu, Linjian Xia, Jinru Cui, Junyuan Mo, Yuan Li, Laixin Xia, Juan Shen, Shan Xiao
Abstract
Stimulant medications are widely prescribed for attention deficit hyperactivity disorder (ADHD) and have significant abuse liability. Here we show that - consistent with clinical data - females exhibit enhanced behavioral sensitivity to stimulants and define sex- and hormone-dependent adaptations in the dopamine system that contribute to these effects. Single-nucleus RNA sequencing of ventral tegmental area dopamine neurons revealed that projections to the nucleus accumbens (NAc) core - compared to other projection populations - were a hub of sexually dimorphic gene expression, including transcripts regulating dopamine synthesis, and transport. These molecular differences coincided with enhanced dopamine release and clearance in females, particularly during phases of the estrous cycle when estradiol levels were high. The stimulants amphetamine (a releaser) and methylphenidate (a reuptake inhibitor) more effectively increased dopamine levels in females under certain conditions. However, amphetamine showed more robust hormone-sensitive regulation, with potency reduced by ovariectomy and restored by direct estradiol replacement in the NAc core. Together, the findings indicate that even within a drug class, drugs with different mechanisms of action can leverage different aspects of sexually dimorphic dopamine function. This distinction highlights that sex differences are not uniform but can be differentially sensitive to drug pharmacology.
Authors
Brooke A. Christensen, Jennifer Tat, Michael Z. Leonard, Soren D. Emerson, Shemuel Roberts, Eleanor B. Holmgren, Ainoa Konomi-Pilkati, Hannah B. Elam, Devan M. Gomez, Lin Zheng, Hye Jean Yoon, Sofia H. Lago, Abigail L. Carr, Lillian J. Brady, Maxime Chevée, Erin S. Calipari
Abstract
Stress promotes the progression from borderline hypertension to sustained hypertension, but the mechanism remains unclear. We investigated the role of corticotropin-releasing factor (CRF)-expressing neurons in the central nucleus of amygdala (CeA) on arterial blood pressure (ABP) and sympathetic activity of borderline hypertensive rats (BHRs) subjected to chronic unpredictable mild stress (CUMS). CUMS induced sustained hypertension, and led to increased delta-FosB expression as well as enhanced spontaneous and evoked firing of CeA CRF-expressing neurons in BHRs. Furthermore, optogenetic activation of CeA CRF-expressing neurons significantly increased the sympathetic outflow and ABP in BHRs. Impaired GABAergic inhibition, a depolarizing shift of GABA reversal potential (EGABA), disrupted chloride homeostasis and increased NKCC1 expression were observed in CeA CRF-expressing neurons in BHRs subjected to CUMS. NKCC1 inhibition with bumetanide restored GABAergic inhibition and chloride homeostasis, normalized neuronal excitability, leading to reduced sympathetic vasomotor tone in CUMS BHRs. These results indicate that NKCC1-mediated disruption of chloride homeostasis in CeA CRF-expressing neurons contributes to elevated sympathetic activity and hypertension under chronic stress. These findings enhance our understanding of the neuronal and molecular mechanisms underlying stress-induced hypertension and reveal potential targets for its prevention and treatment.
Authors
Hongyu Ma, Ying Zhang, Xinqi Guo, Qiyue Zhao, Peiyun Yang, Yan Liu, Yue Guan, Yan Wei, Huijie Ma
Abstract
Enteric nervous system (ENS) injury, characterized by progressive degeneration of enteric neurons and glial cells, is a common diabetic complication with no effective cure beyond symptomatic management. Enteric neural precursor cells (ENPCs) play a key role in maintaining neurogenesis and gliogenesis within the adult ENS. Here, we demonstrate that bone marrow mesenchymal stem cell–derived microvesicles (BMSC-MVs) alleviate diabetic ENS injury. In both diabetic patients and mouse models, gastrointestinal transit was delayed, ENS structure was impaired, and neurogenesis and gliogenesis from ENPCs were elevated yet remained functionally insufficient. Transcriptomic profiling revealed activation of ER stress and the pro-apoptotic PERK branch of the unfolded protein response in ENPCs. BMSC-MVs homed to the colon, were internalized by ENPCs, and suppressed ER stress, thereby enhancing functional neurogenesis and gliogenesis, restoring ENS structure, and improving gastrointestinal motility. Mechanistically, vinculin on BMSC-MVs bound talin-1 on ENPCs, activating the ERK pathway to suppress diabetic ER stress. These results identify BMSC-MVs as a promising cell-free therapeutic strategy for diabetic ENS injury.
Authors
Huiying Shi, Hailing Yao, Yilin Liu, Mengke Fan, Sicheng Cai, Shizhao Xu, Chen Jiang, Yurui Zhang, Weiwei Jiang, Wei Qian, Rong Lin
Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and striatal neuron degeneration, primarily affecting medium spiny neurons (MSNs). Despite extensive research, the underlying metabolic vulnerabilities contributing to HD pathogenesis remain poorly understood. In this study, we employ RNA sequencing (RNA-seq) and metabolomics analyses to identify marked dysregulation of one-carbon metabolism in HD. We validate that SHMT2, a key mitochondrial enzyme in the mitochondrial one-carbon (mt-1C) pathway, is substantially downregulated in HD patient-derived iPSC-differentiated human striatal organoids (hSOs) and YAC128 mice. Functionally, pharmacological inhibition or genetic deletion of SHMT2 exacerbates mutant huntingtin (mHTT) aggregation, induces MSN degeneration in hSOs, and impairs motor function in WT mice. Conversely, SHMT2 overexpression attenuates MSN degeneration in HD-hSOs and improves motor performance in YAC128 mice. Mechanistically, SHMT2 deficiency leads to homocysteine (HCY) accumulation, which interacts with AARS1 and suppresses histone lactylation, thereby perturbing transcriptional regulation and associating with neurodegenerative phenotypes. Finally, we demonstrate that the HD clinical drug haloperidol modulates SHMT2 expression and restores histone lactylation, providing a pharmacological tool to probe SHMT2-dependent metabolic and epigenetic regulation in HD models. These findings highlight a metabolic-epigenetic axis as a promising therapeutic target for HD.
Authors
Mingqin Lu, Kexin Li, Shanshan Wu, Zhilong Zheng, Xinyue Li, Shengda Wang, Hanwen Yu, Chunyue Liu, Yueqing Jiang, Xueqin Song, Yan Liu, Xing Guo
Abstract
The mammalian brain relies primarily on glucose for its energy needs. Delivery of this nutrient to the brain is mediated by the glucose transporter-1 (GLUT1) protein. Low GLUT1 thwarts glucose entry into the brain, causing an energy crisis and, triggering, in one instance, the debilitating neurodevelopmental condition – GLUT1 deficiency syndrome (GLUT1DS). Current treatments for GLUT1DS are sub-optimal, as none address the root cause – low GLUT1 – of the condition. Levels of this transporter must respond rapidly to the brain’s changing energy requirements. This necessitates fine-tuning its expression. Here we describe a long-noncoding RNA (lncRNA) antisense to GLUT1 (SLC2A1) and show that it is involved in such regulation. Raising levels of the lncRNA had a concordant effect on GLUT1 in cultured human cells and transgenic mice; reducing levels elicited the opposite effect. Delivering the lncRNA to GLUT1DS model mice via viral vectors induced GLUT1 expression, enhancing brain glucose levels to mitigate disease. Direct delivery of such a lncRNA to combat disease has not been reported previously and constitutes, to our knowledge, a unique therapeutic paradigm. Moreover, considering the importance of maintaining homeostatic GLUT1 levels, calibrating transporter expression via the lncRNA could become broadly relevant to myriad conditions, including Alzheimer’s disease, wherein GLUT1 is perturbed.
Authors
Maoxue Tang, Sasa Teng, Yueqing Peng, Ashley Y. Kim, Yoon-Ra Her, Peter Canoll, Jeffrey N. Bruce, Phyllis L. Faust, Kailash Adhikari, Darryl C. De Vivo, Umrao R. Monani
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)