Journal of Molecular Neuroscience最新文献

{"title":"Severe SPTBN4-Related Neurodevelopmental Disorder: Case Report of Two Siblings with Lethal Outcomes","authors":"Maram Abdalla,&nbsp;Lana Mashal,&nbsp;Werner Diehl,&nbsp;Amal Al Tenaiji,&nbsp;Afsheen Raza,&nbsp;Laura M. Winter-Paquette","doi":"10.1007/s12031-026-02498-w","DOIUrl":"10.1007/s12031-026-02498-w","url":null,"abstract":"<div>\u0000 \u0000 <p>Spectrin beta non-erythrocytic 4 (SPTBN4) disorder is a rare yet impactful condition that is also known as neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND). It is caused by homozygous or compound heterozygous mutations in the <i>SPTBN4</i> gene, which encodes beta IV (βIV) spectrin primarily found in neurons and pancreatic islets. Here, we report two male siblings from a Syrian non-consanguineous (possibly distantly related) family diagnosed with SPTBN4 disorder. Both patients exhibited severe failure to thrive, hypotonia, dysphagia, and global developmental delay, initially suggesting spinal muscular atrophy (SMA). Further testing has ruled out SMA for both patients, and the older sibling died undiagnosed at the age of 1 year and 6 months. Subsequently, whole genome sequencing (WGS) revealed a novel homozygous nonsense c.508 A &gt; T p. (Lys170*) variant in the <i>SPTBN4</i> gene in the younger sibling, and he died at the age of 2 years and 7 months with a presumed diagnosis of NEDHND. Upon the confirmation of the mutation in DNA stored from the older sibling, the variant was reclassified from a variant of uncertain significance (VUS) to likely pathogenic, enabling prenatal genetics testing for future pregnancies. This case study reports a novel lethal genetic variant in the <i>SPTBN4</i> gene in two siblings, capturing their clinical progression, and comparing them with recent cases to highlight both common and unique features associated with NEDHND. The report’s findings provide valuable insights into the UAE cohort, contributing to the limited body of knowledge on variants present in Arab populations.</p>\u0000 </div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147796393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Involvement of t-SNARE Proteins and Signaling Pathways During PGE2-Induced TRPV1 Sensitization","authors":"Sahar M. Jaffal,&nbsp;Samer Alqaralleh,&nbsp;Munther S. Alnajjar","doi":"10.1007/s12031-026-02529-6","DOIUrl":"10.1007/s12031-026-02529-6","url":null,"abstract":"<div><p>Prostaglandin E2 (PGE2) is a significant mediator of inflammatory pain that causes sensitization of the transient receptor potential vanilloid 1 (TRPV1) channels in primary sensory neurons. Previous research focused on intracellular signaling pathways; however, the role of vesicular trafficking mechanisms in TRPV1 sensitization is not fully elucidated. In this study, we examined whether PGE2-induced TRPV1 sensitization correlates with distinct regulation of t-SNARE proteins in dorsal root ganglia (DRG) and peripheral tissues, utilizing a rat model of inflammatory pain. We used behavioral tests, different inhibitors, DRG neuronal cultures, and protein expression tests. We observed that PGE2-induced sensitization correlates with a reduction in SNAP25 expression in DRG neurons and a decrease in syntaxin-1 expression in peripheral tissues. Pharmacological inhibition of various signaling pathways diminished PGE2-induced hyperalgesia in hyperalgesic priming model and modified t-SNARE protein expression. These results suggest, rather than definitively establish, the involvement of the following signaling pathways in capsaicin-induced mechanical allodynia: PKCε, cAMP, PLC, SNAP25, p38 MAPK, JNK MAPK, ERK-MAPK, PKC, PKA, CaMKII, CDK5, intracellular and extracellular Ca²⁺. The differential regulation of t-SNARE proteins may be linked to TRPV1 sensitization in a tissue-specific manner. Nonetheless, since only total protein levels were evaluated and no direct measurements of membrane trafficking were conducted, additional studies are necessary to elucidate the mechanistic role of t-SNARE proteins in TRPV1 surface localization and function.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147796897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the Clinical Spectrum of LYRM7-Associated Mitochondrial Complex III Deficiency: Insights from New Cases and Literature Review","authors":"Golazin Shahbodagh Khan,&nbsp;Shiva Bayat,&nbsp;Reza Azizimalamiri,&nbsp;Mohammad Nikoohemmat,&nbsp;Narges Mashayekhi,&nbsp;Sahar Nabilou,&nbsp;Ali Reza Tavasoli,&nbsp;Mahmoud Reza Ashrafi,&nbsp;Morteza Heidari","doi":"10.1007/s12031-026-02527-8","DOIUrl":"10.1007/s12031-026-02527-8","url":null,"abstract":"<div><p>Mitochondrial complex III (CIII) deficiency, resulting from abnormalities in its subunits or assembly factors, presents with diverse clinical manifestations. LYRM7-associated CIII deficiency is rare and typically presents with progressive neurodegeneration. We report a case series of <i>LYRM7</i>-associated CIII deficiency in two brothers, highlighting inflammatory demyelinating-like presentations, intrafamilial variability, and atypical disease progression. We present an investigational case series highlighting continuing challenges in diagnosing and managing <i>LYRM7</i>-associated mitochondrial complex III deficiency. Whole-exome sequencing (WES) was performed for diagnostic evaluation, followed by confirmatory Sanger sequencing and literature review of previously reported cases. Two brothers from a consanguineous family presented with ataxia, visual impairment, and progressive neurological deterioration including spasticity, seizures, cognitive decline, and motor weakness. Patient 1 (P1) experienced recurrent ataxic episodes beginning at 7 years of age, initially suspected to represent an inflammatory demyelinating disorder, while patient 2 (P2) demonstrated a more aggressive disease course with rapid neurological deterioration and early mortality at 8 years of age. Neuroimaging revealed cystic white matter changes suggestive of mitochondrial leukodystrophy and longitudinally extensive transverse myelitis (LETM) in both patients, differing from typical inflammatory demyelinating patterns. Genetic testing confirmed a pathogenic <i>LYRM7</i> variant. Notably, intrafamilial clinical variability and the inflammatory-like presentation in P1- including LETM and optic neuritis mimicking neuromyelitis optica spectrum disorder (NMOSD)- distinguished our cases from previously reported patients. These findings expand the phenotypic spectrum of <i>LYRM7</i>-associated CIII deficiency and highlight diagnostic challenges. This case series expand the clinical spectrum of <i>LYRM7</i>-associated complex III deficiency and highlights relapsing inflammatory-like presentations as a potential diagnostic pitfall. Our findings emphasize the importance of considering mitochondrial disorders in children presenting with recurrent demyelinating-like episodes, atypical progression, or familial patterns. Early genetic diagnosis is essential for accurate diagnosis, counseling, and management of mitochondrial disorders. </p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective Effects of Semaglutide in Cyclophosphamide-Induced Neuropathy: Restoring SIRT1/AMPK, PI3K/AKT/mTOR, and Antioxidant Pathways","authors":"Hossein M. Elbadawy,&nbsp;Mohannad A. Almikhlafi,&nbsp;Tahani Saeedi,&nbsp;Mohammed H. Alsubhi,&nbsp;Abdulrahman A. Aljabri,&nbsp;Yosra Assem Hussien,&nbsp;Mevidette Elmadani,&nbsp;Hany M. Fayed,&nbsp;Rehab F. Abdel-Rahman","doi":"10.1007/s12031-026-02521-0","DOIUrl":"10.1007/s12031-026-02521-0","url":null,"abstract":"<div>\u0000 \u0000 <p>Cyclophosphamide (CP), a widely used chemotherapeutic agent, often induces chemotherapy‑induced peripheral neuropathy (CIPN). CP metabolism generates acrolein, a reactive aldehyde that promotes oxidative stress, lipid peroxidation, mitochondrial dysfunction, and NF‑κB–mediated neuroinflammation, while impairing PI3K/AKT/mTOR signaling. These processes drive axonal degeneration, demyelination, and neuronal apoptosis, highlighting the need for novel therapies. This study examined the neuroprotective effects of semaglutide, a glucagon‑like peptide‑1 (GLP‑1) receptor agonist, in a rat model of CP‑induced neuropathy. Wistar rats were assigned to control, CP (200 mg/kg, IP), or CP plus semaglutide (12–40 µg/kg, SC every three days). Motor and sensory functions were assessed using rotarod, hot plate, tail flick, and cold allodynia tests. Sciatic nerves were analyzed for oxidative stress markers (GSH, SOD, MDA), inflammatory cytokines (TNF‑α, IL‑6), apoptotic regulators (Caspase‑3, BAX, Bcl‑2), and signaling proteins (SIRT1, AMPK, PI3K, AKT, mTOR). Histopathology and immunohistochemistry evaluated structural integrity and Nrf2/p‑AKT expression. CP caused marked motor incoordination (‑31.3% rotarod latency) and sensory hypersensitivity (thermal: ‑60.7%; cold: ‑46.6%; tail flick: ‑31.4%). Semaglutide dose‑dependently reversed these deficits, with the higher dose restoring near‑normal function. Mechanistically, semaglutide reduced oxidative stress, upregulated SIRT1 and AMPK, suppressed TNF‑α and IL‑6, rebalanced apoptotic markers, and restored PI3K/AKT/mTOR signaling. Histology confirmed protection against edema and demyelination, while immunohistochemistry showed recovery of Nrf2 and p‑AKT. Overall, semaglutide provides multimodal neuroprotection against CP‑induced neuropathy, supporting its potential as a therapeutic candidate for CIPN.</p>\u0000 </div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotinamide Riboside (NR) Supplementation Exerts Neuroprotective Effects in db/db Mouse Model of Type 2 Diabetes","authors":"Eleni Hughes,&nbsp;Keely Barton,&nbsp;Daliya Rizvi,&nbsp;Katelyn Dial,&nbsp;Xiaoxin X. Wang,&nbsp;Komuraiah Myakala,&nbsp;Brent T. Harris,&nbsp;G. William Rebeck,&nbsp;Moshe Levi","doi":"10.1007/s12031-026-02499-9","DOIUrl":"10.1007/s12031-026-02499-9","url":null,"abstract":"<div><p>Type 2 diabetes is linked to neuropsychiatric complications such as anxiety-like behaviors, disrupted brain metabolism, neuroinflammation, and impaired mitochondrial function. Nicotinamide riboside (NR) has emerged as a potential therapeutic agent for these complications due to its role in NAD + biosynthesis and neuroprotective properties. In this study, we assessed whether NR supplementation can ameliorate anxiety-like behavior in a mouse model of type 2 diabetes by modulating the hippocampal inflammatory response. 8-week-old db/db mice on the BKS background were used as a model of type 2 diabetes, and db/m mice were used as non-diabetic controls. Four groups, consisting of non-diabetic and diabetic mice, were fed with a control diet or a diet supplemented with NR at 500 mg/kg dosage for 20 weeks. The open field test and nesting behavioral assessments were conducted to evaluate anxiety-related behaviors and overall well-being. After animals were euthanized, biochemical analyses were performed on hippocampal samples using RT-qPCR, Western blotting, and immunohistochemistry. Behavioral assessments revealed increased anxiety and reduced nest-building motivation in db/db mice compared with control mice. These effects were ameliorated by NR treatment. Biochemical analyses revealed that NR attenuated markers of inflammation, including astrocytosis and microglial activation, activation of inflammatory signaling via STING and NF-kB, and pro-inflammatory cytokines. Our findings show that NR supplementation reduces anxiety-like symptoms and neuroinflammation in diabetic mice, highlighting the potential therapeutic relevance of NR in mitigating neuropsychiatric complications associated with diabetes mellitus.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Cutaneous α-Synuclein Pathology as a Differential Marker: A Histological and Statistical Comparison across Neurodegenerative Disease Groups","authors":"Dorota Šebelová,&nbsp;Kateřina Menšíková,&nbsp;Michaela Kaiserová,&nbsp;Lenka Satke,&nbsp;Zuzana Grambalová,&nbsp;Kateřina Čížková,&nbsp;Zdeněk Tauber,&nbsp;Kateřina Klíčová,&nbsp;Dominik Hraboš,&nbsp;Sarah E. V. Cook,&nbsp;Jana Zapletalová,&nbsp;Petr Kaňovský","doi":"10.1007/s12031-026-02515-y","DOIUrl":"10.1007/s12031-026-02515-y","url":null,"abstract":"","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13121578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construction of a Computationally Inferred Single-Cell miRNA Activity Atlas and Analysis of Regulatory Networks in Spinal Cord Injury","authors":"Changli Xu,&nbsp;Bingxuan Wang,&nbsp;Zhengqiang Li,&nbsp;Suchi Qiao,&nbsp;Jianli Bu","doi":"10.1007/s12031-026-02528-7","DOIUrl":"10.1007/s12031-026-02528-7","url":null,"abstract":"<div>\u0000 \u0000 <p>Background. Spinal cord injury (SCI) is a debilitating neurological disorder characterized by complex pathological processes involving dynamic responses of multiple cell types and intricate regulatory networks. Although single-cell RNA sequencing (scRNA-seq) has been employed to dissect cellular heterogeneity in SCI, the activity and regulatory functions of microRNAs (miRNAs) at single-cell resolution remain largely unexplored. Methods. This study utilized the GSE189070 dataset, integrating single-cell transcriptomic data from mouse spinal cord tissues at eight time points: uninjured control and 0.5, 1, 3, 7, 14, 60, and 90 days post-injury. Following quality control, batch correction, and cell-type annotation, miRNA activities across 12 major cell types were computationally inferred using a motif enrichment-based approach. Temporal clustering of miRNA activity was performed with Mfuzz, and subsequent analyses included target gene prediction, functional enrichment, and network construction. Inferred miRNA activity patterns were validated using an independent bulk miRNA sequencing dataset (GSE90452). Key findings were experimentally verified in BV-2 microglial cells and C8-D1A astrocytes using miRNA inhibitors and mimics. Results. We successfully constructed a single-cell transcriptomic atlas and a dynamic computationally inferred miRNA activity landscape during SCI progression. Independent dataset validation confirmed that inferred miRNA activity changes (e.g., mmu-miR-488-3p, mmu-miR-132-3p) were consistent with actual miRNA expression alterations. Our analysis revealed that microglia and macrophages exhibited dynamic miRNA activity patterns closely associated with inflammatory pathways, including TNFA_SIGNALING_VIA_NFKB and TOLL-LIKE RECEPTOR signaling. Cross-cell-type comparison identified 38 common differentially active miRNAs shared between microglia and macrophages, with network analysis revealing coordinated regulation of key inflammatory genes (e.g., Lif, Csf1, Il18rap). In astrocytes, specific miRNAs (e.g., miR-7a-5p, miR-124-3p) were found to regulate apoptotic pathways by targeting Casp3 and Bcl2 family genes. Experimental validation confirmed that miR-130a-3p promotes microglial inflammation, while miR-7a-5p inhibits astrocyte apoptosis under oxidative stress. Conclusion. This study presents a computationally inferred, experimentally validated single-cell-resolution map of miRNA activity dynamics during SCI, revealing potential regulatory networks in key cell types. The concordance between computational inference and independent experimental data supports the biological plausibility of our findings and provides a foundation for further therapeutic exploration.</p>\u0000 </div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the Gut-Brain Axis: Fusobacteriaceae Promotes Parkinson’s Disease Development via CA9 Suppression-Induced Ferroptosis","authors":"Ren Zihan,&nbsp;Li Pengfei,&nbsp;Cao Jingsi","doi":"10.1007/s12031-026-02530-z","DOIUrl":"10.1007/s12031-026-02530-z","url":null,"abstract":"&lt;div&gt;&lt;p&gt;The conceptual framework of the ‘gut-brain axis’ proposes that an imbalance in the gut microbiota plays a contributory role in the etiology of Parkinson’s disease (PD). However, the specific molecular mechanisms, particularly those involving ferroptosis, remain largely unknown. We adopted a robust two-sample Mendelian randomization (MR) strategy, analyzing extensive summary-level GWAS data to unravel the causal connections tying the gut microbiota and ferroptosis-associated proteins to the risk of PD. Our analysis pinpointed 22 distinct gut microbial taxa and five proteins involved in ferroptosis that are genetically predicted to influence PD susceptibility. Notably, the family &lt;i&gt;Fusobacteriaceae&lt;/i&gt; was identified as a robust risk factor. Further mediation analysis suggested that the ferroptosis-related protein carbonic anhydrase 9 (CA9) mediates the genetically predicted effect of &lt;i&gt;Fusobacteriaceae&lt;/i&gt; on PD. Specifically, an elevated genetic predisposition to &lt;i&gt;Fusobacteriaceae&lt;/i&gt; is associated with a downregulation of plasma CA9, a molecular shift that is genetically predicted to heighten the risk of developing PD. The calculated mediation proportion was 11.7%, and the robustness of this result was upheld by comprehensive sensitivity assessments. This study provides novel genetic evidence supporting a potential “gut microbiota–ferroptosis–PD” axis. We propose that &lt;i&gt;Fusobacteriaceae&lt;/i&gt; may aggravate PD progression by downregulating CA9, thereby compromising CA9-dependent anti-ferroptotic defense mechanisms. Collectively, our results provide fresh perspectives on the molecular mechanisms underpinning the gut-brain axis, highlighting promising avenues for therapeutic intervention in PD. &lt;/p&gt;&lt;h3&gt;Graphical Abstract&lt;/h3&gt;&lt;p&gt;The proposed Fusobacteriaceae-CA9-Ferroptosis axis in Parkinson’s disease pathogenesis. A genetically predicted overabundance of Fusobacteriaceae compromises intestinal barrier integrity, facilitating the systemic translocation of lipopolysaccharides (LPS). Upon crossing the blood-brain barrier (BBB), circulating LPS triggers microglial activation and the sustained release of pro-inflammatory cytokines (e.g., TNF-α, IL-1β). This chronic neuroinflammatory microenvironment represses the transcription and expression of the pH-regulating protein carbonic anhydrase 9 (CA9) in dopaminergic neurons. The subsequent CA9 downregulation induces severe intracellular acidification, which dualistically expands the labile iron pool (LIP) via ferritin degradation and cripples the antioxidant defense system by depleting glutathione (GSH) and inactivating GPX4. Ultimately, the confluence of elevated ferrous iron (Fe²⁺) and an acidic milieu aggressively accelerates the Fenton reaction, driving massive lipid peroxidation of polyunsaturated fatty acids (PUFAs) and culminating in neuronal ferroptosis&lt;/p&gt;&lt;div&gt;&lt;figure&gt;&lt;div&gt;&lt;div&gt;&lt;picture&gt;&lt;source&gt;&lt;img&gt;&lt;/source&gt;&lt;/picture&gt;&lt;span&gt;The alternative text for this image may have been generated usin","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reimagining GSK-3β Therapeutics in Alzheimer’s Disease: From Inhibition to Activity Normalization and Targeted Degradation","authors":"Emad Manni,&nbsp;Hayder M. Al-kuraishy,&nbsp;Rabab Eisawy,&nbsp;Ahmed M. Abdelaziz,&nbsp;Gaber El-Saber Batiha","doi":"10.1007/s12031-026-02518-9","DOIUrl":"10.1007/s12031-026-02518-9","url":null,"abstract":"<div>\u0000 \u0000 <p>Glycogen Synthase Kinase-3β (GSK-3β) acts as a critical pathogenic amplifier in Alzheimer’s disease (AD), linking and intensifying various degenerative processes such as amyloid-β formation, tau hyperphosphorylation, and neuroinflammation. Rather than serving solely as an upstream trigger, the hyperactivity of GSK-3β interacts with other dysregulated kinases, including CDK5, DYRK1A, and MARKs, to worsen neurodegeneration. This collaboration leads to increased neuronal cell death and cognitive decline in AD patients. However, the clinical translation of conventional GSK-3β inhibitors has been thwarted by a fundamental paradox: complete enzymatic blockade induces Wnt-mediated toxicity, while partial inhibition often fails due to compensatory feedback. This review argues for a paradigm shift: from broad kinase suppression to precise activity normalization. We critically analyze the translational failures of catalytic inhibitors, then examine emerging strategies capable of restoring physiological kinase homeostasis. Foremost among these are brain-penetrant Proteolysis-Targeting Chimeras (PROTACs), which eliminate both the catalytic and non-catalytic (scaffold) functions of GSK-3β through targeted proteasomal degradation, thereby addressing pathological activities that conventional inhibitors leave intact. Furthermore, we explore the synergistic potential of multi-target-directed ligands (MTDLs) and indirect modulation via the gut-brain axis to widen the therapeutic window. By recalibrating rather than silencing GSK-3β, this framework outlines a mechanistically grounded roadmap for achieving safe and effective disease modification in AD, moving this central kinase from an undruggable liability to a central component of future therapeutic strategies.</p>\u0000 </div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147738385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sesn2 is Associated with Attenuated Muscle Atrophy and Altered Expression of Key Myogenic and Autophagy Markers in Mdx Mice","authors":"Zubiao Song,&nbsp;Qing Lin,&nbsp;Jiahui Liang,&nbsp;Juanjuan He,&nbsp;Weixi Zhang","doi":"10.1007/s12031-026-02522-z","DOIUrl":"10.1007/s12031-026-02522-z","url":null,"abstract":"<div>\u0000 \u0000 <p>Duchenne muscular dystrophy (DMD) is a common lethal neuromuscular disorder which is characterized by progressive skeletal muscle atrophy. Despite the beneficial role of Sestrin2 (Sesn2) in improving denervation-induced skeletal muscle atrophy, the effect of Sesn2 on the skeletal muscle of DMD remains largely unknown. To regulate the expression of Sesn2, we systemically modulated its expression in <i>mdx</i> mice via tail-vein injection of AAV9 vectors. The tibialis anterior (TA) muscles were subsequently harvested for analysis by immunofluorescence and Western blotting to assess myofiber morphology and the protein levels of key markers of atrophy, myogenesis, and autophagy. In this study, we found that the expression levels of Sesn2 were significantly upregulated in the tibialis anterior muscle of <i>mdx</i> mice. Sesn2 overexpression was associated with increased myofiber cross-sectional area and reduced levels of the atrophy-related markers MuRF1 and Atrogin-1, whereas Sesn2 knockdown aggravated the expression of MuRF1 and Atrogin-1. At the molecular level, Sesn2 overexpression significantly upregulated the expression of myogenic differentiation factors (Myog and Myf5), whereas its knockdown significantly downregulated them, indicating the positive regulatory effect of Sesn2 on myogenic signaling. Additionally, the inhibition of Sesn2 significantly suppressed key autophagy markers (downregulation of pUlk1, Bec1 and LC3-II expression and accumulation of p62). Collectively, these data suggest that Sesn2 is associated with improvement in dystrophic muscle histology by coordinately influencing cellular process related to protein degradation, myogenesis and autophagy, presenting it as a potential therapeutic candidate for DMD.</p>\u0000 </div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147737857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}