Neuroscience
Abstract
Spinocerebellar Ataxia Type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in the gene encoding protein kinase C gamma (PKCγ), a Ca2+/diacylglycerol (DG)-dependent serine/threonine kinase dominantly expressed in cerebellar Purkinje cells. These mutations impair autoinhibitory constraints to increase the basal activity of the kinase, resulting in deficits in the cerebellum that are not observed upon simple deletion of the gene, and severe ataxia. To better understand the impact of aberrant PKCγ signaling in disease pathology, we developed a knock-in murine model of the SCA14 mutation ΔF48 in PKCγ. This fully-penetrant mutation is severe in humans and is mechanistically informative as it has high basal activity but is unresponsive to agonist stimulation. Genetic, behavioral, and molecular testing revealed that ΔF48 PKCγ mice have ataxia-related phenotypes and an altered cerebellar phosphoproteome driven primarily by enhanced Ca2+/calmodulin-dependent Kinase II (CaMKII) signaling, effects that were more severe in male mice. Analysis of existing human data revealed that SCA14 has a significantly earlier age of onset for males compared with females. Data from this clinically relevant mutation suggested that enhanced basal activity of PKCγ is sufficient to cause ataxia and that treatment strategies to modulate aberrant PKCγ may be particularly beneficial in males.
Authors
Sarah A. Wolfe, Yuliang Ma, Tomer M. Yaron-Barir, Carly Chang, Caila A. Pilo, Majid Ghassemian, Amanda J. Roberts, Sang Ryeul Lee, Benjamin A. Henson, Kristen Jepsen, Jared L. Johnson, Lewis C. Cantley, Susan S. Taylor, George Gorrie, Alexandra C. Newton
Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine (CAG) repeat in the N-terminal of the Huntingtin protein (HTT). Microglial activation and elevated pro-inflammatory cytokines are observed in HD brains, but the mechanisms regulating neuroinflammation and microglial activation are poorly understood. Metformin-mediated neuroprotection has been demonstrated in experimental models of neurodegeneration, including HD. We found that metformin inhibits mitochondrial DNA (mtDNA) release and subsequent neuroinflammation in the cortex and striatum of a mouse model of HD. Moreover, elevated pro-inflammatory cytokines and microglial activation are inhibited by metformin in HD transgenic mice brain. Metformin reduced pathological microglial clusters and shifted towards a quiescent, homeostatic phenotype. Metformin improved aberrant immunometabolism in HD mouse brain and primary microglia. Mechanistically found that metformin regulates mitochondrial fission, reprograms deregulated metabolism in HD microglia, and controls microglial activation and inflammation in HD transgenic mice.
Authors
Abhishek Jauhari, Adam C. Monek, Olena S. Abakumova, Tanisha Singh, Sukhman Singh, Xiaomin Wang, Carley S. Clise, Diane L. Carlisle, Robert M. Friedlander
Abstract
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene leading to decreased SMN protein levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. SMN deficiency resulted in downregulation of kinesin heavy chain isoform 5A (KIF5A) in human neurons and in a mouse model of SMA. SMN associated with KIF5A mRNA and contributed to its stability. Reduced SMN levels impaired axon regeneration, which was rescued by KIF5A overexpression. Because KIF5A has also been connected to ALS, these findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as an SMN regulated factor. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.
Authors
Tetsuya Akiyama, Yi Zeng, Caiwei Guo, Olivia Gautier, Lauren Koepke, Heankel Lyons, Elana Molotsky, Juliane S. Bombosch, Odilia Sianto, Jay P. Ross, Phuong Hoang, Luke Zhao, Cole Spencer, Charlotte J. Sumner, Michelle Monje, John W. Day, Aaron D. Gitler
Abstract
N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional epigenetic modification in mammalian mRNAs, and it has been implicated in the regulation of nervous system development by modulating mRNA metabolism. VIRMA is the largest core subunit of the m6A methyltransferase complex and essential for the assembly and stability of the m6A methyltransferase complex. In the retina, m6A methylation modification is widely distributed in various cellular layers and is essential for retinal homeostasis. Here, we demonstrate that VIRMA-mediated m6A modification is essential for retinal homeostasis. Loss of Virma in retinal rod cells resulted in abnormal reduction in m6A methylation levels, along with impaired photoreceptor function and degeneration. Mechanically, Virma depletion in photoreceptors dampened the m6A modification level of visual perception-associated genes, resulting compromised visual function and photoreceptors degeneration. Moreover, Virma interacts with splicing factor to regulate the alternative splicing events of retina function-related genes such as Polg2, which contributes to photoreceptor damage. Reintroduction of normal Virma expression colonially rescued photoreceptor degeneration. Collectively, our data elucidate the important role of Virma-mediated m6A modification in photoreceptor function and suggest that epigenetic modulation could serve as potential targets to treat these blinding diseases.
Authors
Wenjing Liu, Xiaojing Wu, Rong Zou, Fan Zhang, Yudi Fan, Kuanxiang Sun, Liping Yang, Jiang Hu, Lin Zhang, Xianjun Zhu
Abstract
Sleep disturbance is a prevalent yet poorly understood comorbidity in autism spectrum disorders (ASD). Here, we uncover a bidirectional regulatory axis connecting the ASD risk gene POGZ to core circadian mechanisms. We demonstrate that Pogz is widely expressed in the suprachiasmatic nucleus (SCN), the central pacemaker of the circadian rhythms and exhibits circadian oscillations in both the hypothalamus and liver with its transcription directly regulated by the circadian molecule DBP through a D-box element in its proximal enhancer. Pogz-deficient mice exhibited prolonged circadian periodicity, impaired light-induced phase shift, delayed adaption to an 8-hour advance jet-lag, and reduced SCN c-Fos activation in response to light pulses. Mechanistically, POGZ interacts with and enhances the transcription activity of CREB, a key regulator of light-induced phase resetting. Notably, Pogz deletion leads to ASD-related deficits in social novelty and cognition, with cognitive impairments influenced by both photoperiod and behavioral paradigm. Our findings thus reveal a critical, previously unrecognized intersection between an ASD risk gene and circadian clock, offering new insights into the pathogenesis of core ASD symptoms and comorbid sleep disturbances.
Authors
Ting Wu, Jiao He, Chu-Jun Xu, Chi-Yu Li, Pingchuan Zhang, Yanfeng Wang, Shanshan Zhu, Lusi Zhang, Jingtan Zhu, Jing Zhang, Jia-Da Li, Huadie Liu
Abstract
Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the gene encoding huntingtin. Since accumulation of mutant huntingtin (mHtt) leads to dysfunction of numerous cellular pathways and toxicity, reducing levels of the mutant protein represents a key therapeutic objective in HD. We found that ubiquitination of mHtt by E3 ubiquitin ligase Nedd4 promotes clearance of the mutant protein. Knockdown of Nedd4 increased toxicity of mHtt in mouse primary neurons and in a fly model of HD, suggesting the protective role of Nedd4. Importantly, levels of Nedd4 were decreased in mHtt-expressing neurons through impaired mTORC1 activity, suggesting a feedback loop of mHtt accumulation and Nedd4 reduction that leads to accumulation and, ultimately, toxicity of mHtt. These findings suggest that restoring Nedd4 activity may offer a novel therapeutic opportunity for HD.
Authors
Hyunkyung Jeong, Yiyang Qin, Fangke Xu, Katarina Trajkovic, Myung Jong Kim, Nicolas Marotta, Kana Hamada, Ravi Allada, Su Yang, Dimitri Krainc
Abstract
Among the known genetic causes of syndromic autism spectrum disorders (ASDs) are transcription factor deficiencies. In this regard, haploinsufficiency of the zinc finger and broad complex, tramtrack, bric and brac domain–containing protein 20 (ZBTB20) leads to a prototypical clinical picture, referred to as Primrose syndrome, comprising severe ASD symptoms together with intellectual disability. Here, we present a comprehensive behavioral and phenotypical characterization of Zbtb20+/– mice, a construct valid model of this thus far untreatable human condition. Zbtb20+/– mice exhibited diminished sociability, reduced vocalization, distinct repetitive behaviors, impaired cognitive flexibility, hyperactivity, and hypoalgesia. Magnetic resonance imaging revealed increased volumes of hippocampus, cerebellum, brain matter, and whole brain, confirmed by postmortem brain weight measurements. Due to our previous observation of enhanced ZBTB20 expression in CA1 pyramidal neurons upon recombinant human erythropoietin (rhEPO) injections, we anticipated a mitigating effect through rhEPO treatment of Zbtb20 deficiency/Primrose syndrome. Indeed, after 3 weeks of alternate-day rhEPO injections, a remarkable improvement in the behavioral phenotype was observed. Our results highlight rhEPO as promising treatment for Primrose syndrome.
Authors
Martin Hindermann, Justus B.H. Wilke, Yasmina Curto, Stefan N. Oline, Vinicius Daguano Gastaldi, Umer Javed Butt, Rakshit Dadarwal, Umut Çakır, Anja Ronnenberg, Kurt Hammerschmidt, Susann Boretius, Anastassia Stoykova, Anton B. Tonchev, Klaus-Armin Nave, Manvendra Singh, Hannelore Ehrenreich
Abstract
Pancreatic cancer is a highly innervated gastrointestinal disease in which sympathetic nerves play a critical role in modulating tumor growth and the tumor microenvironment (TME). While recent studies suggest that sympathetic nerves influence various TME components, including lymphoid and myeloid immune cells, their interactions with cancer-associated fibroblasts (CAFs) remain poorly understood. CAFs are a hallmark of pancreatic tumors and are known to upregulate axon guidance and neuroactive cues, suggesting a potential feedback loop with tumor-innervating nerves. Here, we investigated the bidirectional crosstalk between sympathetic nerves and CAFs in human and mouse pancreatic tumors. Using a chemo-genetic ablation model, we selectively eliminated pancreatic sympathetic nerves and found that denervation significantly reduced tumor size in female mice. To further dissect this interaction, we established co-culture systems with immortalized pancreatic fibroblasts and primary sympathetic neuron explants, identifying key transcriptional changes driven by CAF-sympathetic nerve signaling. Our findings demonstrated that sympathetic signaling enhanced CAF activation and extracellular matrix remodeling, while activated CAFs, in turn, induced transcriptional programs in sympathetic neurons associated with nerve injury response. These results establish CAFs as central mediators of the tumor-supportive role of sympathetic nerves, offering further insights into the neural regulation of pancreatic cancer progression.
Authors
Ariana L. Sattler, Parham Diba, Kevin Hawthorne, Carl Pelz, Joe Grieco, Tetiana Korzun, Bryan Chong, M.J. Kuykendall, Rosalie C. Sears, Daniel L. Marks, Mara H. Sherman, Teresa A Zimmers, S. Ece Eksi
Abstract
Oxidative signaling is a central mechanism in alcohol-induced injury and has a strong implication in blood-brain barrier (BBB) dysregulation and neuroinflammation. Here, by targeting oxidative signaling, we hypothesized an innovative approach to develop a clinically relevant therapeutic strategy for alleviating alcohol-mediated neurovascular damage. To accomplish this, we enhanced the endogenous activity of Nrf2 (nuclear factor E2-related factor 2) by treating with an Nrf2 activator III TAT peptide (Nrf2 peptide, NP) and investigated the neuroprotective role of Nrf2 in promoting antioxidant defense properties and reducing BBB damage and transmigration of leukocytes to the brain following alcohol ingestion. We administered the NP subcutaneously to alcohol-ingested mice and evaluated its therapeutic potential in alleviating alcohol-associated neurovascular impairments. We compared the results with control peptide (random sequence with TAT)-treated animals. The studies showed that the NP treatment preserved the oxidant-antioxidant balance, downregulated ICAM-1 and its receptors, and mitigated BBB damage and leukocyte infiltration into the brain. We validated the effect of the NP in Nrf2 knock-out (KO) mice (Nrf2−/−). Thus, this study demonstrates NP’s neurovascular protective effects by regulating the oxidant-antioxidant balance, reducing oxidative stress-induced BBB disruption, and limiting transmigration of immune cells to the brain in a mouse model of alcohol ingestion.
Authors
Bibhuti B. Saikia, Saleena Alikunju, Yemin A. Poovanthodi, Zayan Kassim, P. M. Abdul Muneer
Abstract
Hirschsprung disease (HSCR) is a congenital intestinal disorder characterized by the absence of ganglia in the distal intestine. Despite surgical resection of the aganglionic intestine and pull-through surgery, HSCR patients still experience bowel dysfunction, indicating that latent abnormalities may also exist in the proximal ganglionic intestine. To elucidate possible causes of postoperative bowel dysfunction in HSCR, we investigated differences in the proximal ganglionic intestine using an animal model of HSCR (Ednrb-null mice) and validated our findings in tissue from human HSCR patients. We found that the proximal ganglionic colon of HSCR mice exhibited greater stiffness and fibrosis than their wild-type littermates. Similarly, submucosal fibrosis was significantly greater in the proximal ganglionic intestine of HSCR patients than in intestinal tissue from age and site-matched controls. Furthermore, we observed dysregulated expression of extracellular matrix (ECM)-related genes in the proximal ganglionic intestine of HSCR mice compared to controls. We conclude that increased fibrosis, stiffness, and alterations in ECM composition may contribute to persistent dysfunction of the ganglionic intestine in HSCR. These findings add to the growing body of literature that describe abnormalities in the proximal ganglionic intestine of HSCR and suggest that HSCR is not limited to the aganglionic intestine alone.
Authors
Prisca C. Obidike, Britney A. Hsu, Chioma Moneme, Oluyinka O. Olutoye II, Walker D. Short, Mary Hui Li, Swathi Balaji, Yuwen Zhang, Sundeep G. Keswani, Lily S. Cheng
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