Jul 2026· Autophagy· pp. 1-24· 0 citations· 84 references
Medicine
TL;DR
Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis, and highlights IL17A inhibition as a promising therapeutic strategy for targeting autophagy-lysosomal dysfunction in HD.
Abstract
Huntington disease (HD) is a progressive neurodegenerative disease caused by an expanded CAG repeat in the HTT (huntingtin) gene, leading to the accumulation of mutant HTT (mHTT). IL17A (interleukin 17A), a proinflammatory cytokine primarily secreted by Th17 and γδ T cells, has been implicated in immune-mediated neurodegeneration. However, the role of IL17A in the pathogenesis of HD remains poorly understood. Here, we identify IL17A as a critical pathogenic factor in HD that promotes neuroinflammation, mHTT aggregation, and autophagy-lysosomal dysfunction. IL17A disrupts autophagic flux by downregulating CTSB and CTSD, inducing SQSTM1/p62 and MAP1LC3B-II/LC3-II accumulation, and impairing lysosomal reformation. Mechanistically, IL17A suppresses lysosomal biogenesis by inhibiting the nuclear translocation of TFE3. This regulation occurs via a novel GSK3B/GSK-3β-TFE3 signaling pathway. Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis. IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF. Moreover, IL17A mAb restores autophagy-lysosomal function by facilitating the clearance of protein aggregates and upregulating lysosomal enzymes and biogenesis markers, including CTSB, CTSD, PIP5K1A, and LAMP2. These findings establish IL17A as a key modulator of HD pathophysiology and highlight IL17A inhibition as a promising therapeutic strategy for targeting autophagy-lysosomal dysfunction in HD.
Mutations in lysosomal enzyme glucocerebrosidase (GBA), the most common genetic risk factor for Parkinson disease (PD), exacerbate α-synuclein pathology through unclear mechanisms. Here, we report, in a large cohort, that GBA-mutated PD patients exhibit lower serum cholesterol levels. By introducing the most common GBA variant in our cohort, L444P, into human α-synuclein knock-in mice, we noted that the mice exhibited behavioral and molecular pathological PD features at 12 months of age. Mechanistically, lysosomal proteomics identified the loss of lysosome-cytoplasmic vesicle interactions and cholesterol-containing lipid microdomains in both PD patients and mice. Autophagic flux monitoring revealed impaired autophagosome-lysosome fusion in GbaL444P/+ neurons. Gain- and loss-of-function experiments uncovered cholesterol synthesis impairment via glycosphingolipid-reduced SREBP2 levels. Importantly, cholesterol supplementation was found to enhance the autophagic flux and mitigate α-synuclein accumulation in vitro, whereas AAV-Srebp2 delivery increased α-synuclein clearance in GbaL444P/+ mice. Our study provides animal models and mechanistic insights into GBA-associated PD and offers a therapeutic paradigm by facilitating cholesterol-associated α-synuclein autophagic clearance.
Mingjia Chen, Fengtao Liu, Yujie Yang et al.· Cell Reports· 0 citations
The RNA binding G3BP1 is depleted in several neurodegenerative diseases, yet its functional consequences at the cellular level remain poorly understood. While best known for its critical role in stress granule formation, we demonstrate that G3BP1 also stabilises the COPI vesicle protein beta-COP by promoting its interaction with the deubiquitinase USP10. G3BP1 depletion disrupts this interaction leading to increased ubiquitination of beta-COP, which accelerates its proteasomal degradation. This leads to compromised Golgi structure and function, and impaired lysosomal homeostasis, which causes defective autophagic flux. Consequently, the autophagic clearance of α-synuclein, a protein that can drive Parkinson's disease (PD), is significantly slowed. Importantly, we observe a concurrent reduction of both G3BP1 and beta-COP protein levels in brain sections from PD and dementia with Lewy Body (DLB) patients and from a PD mouse model. These findings reveal a novel mechanistic link between G3BP1, vesicular trafficking, and proteostasis in neurodegeneration.
Sarayu Ramakrishna, Laura Ryan, S. Son et al.· Cell Death and Differentiati...· 0 citations
Autophagy dysfunction and neuroinflammation are central to Alzheimer’s disease (AD), yet how extracellular amyloid-β (Aβ) couples to impaired autophagic flux and heightened neuroinflammation remains unknown. Here, we identify the TAM receptor AXL as a molecular transducer that couples Aβ sensing to the regulation of autophagy and neuroinflammation in astrocytes. Aβ induces γ-secretase-dependent cleavage of AXL, generating a nuclear intracellular domain (AXL-ICD) that forms phase-separated condensates and activates autophagy gene transcription through SIRT2-mediated recruitment of the RUVBL1/2-INO80 chromatin-remodeling complex. This axis is activated in astrocytes of postmortem AD brains. Concurrently, AXL-ICD binds to the SIRT2 catalytic domain and suppresses its deacetylase activity, increasing α-tubulin acetylation and altering microtubule dynamics. While moderate AXL-ICD levels promote autophagic flux, excessive elevation paradoxically triggers microtubule hyperstabilization, thereby impairing autophagosome-lysosome fusion and causing pathological accumulation of autophagosomes and H2O2. The inhibitory peptide AxSBiP disrupts the AXL-ICD/SIRT2 interaction, restores autophagic flux, reduces plaque burden, and normalizes Aβ-induced H2O2 production and astrogliosis in APP/PS1 mice. We propose the AXL-ICD/SIRT2 axis as an effective therapeutic target to reduce Aβ burden and neuroinflammation in AD.
T. Kim, Mridula Bhalla, Uiyeol Park et al.· bioRxiv· 0 citations
Inflammasomes, particularly the NLRP3 complex, play a central role in coordinating innate immune activation and neuroinflammatory responses within the cytosol. Persistent or dysregulated nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) activation promotes caspase-1-dependent maturation of interleukin (IL)-1β and IL-18 and triggers gasdermin D (GSDMD)-mediated pyroptosis, thereby contributing to the pathogenic cascades underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Endogenous gasotransmitters, including hydrogen sulfide (H2S) and nitric oxide (NO), have emerged as critical modulators of redox homeostasis, mitochondrial function, and inflammatory signaling pathways that directly or indirectly regulate NLRP3 inflammasome activity. Accumulating evidence suggests that these gaseous mediators exert potent neuroprotective effects by attenuating inflammasome activation, limiting oxidative and nitrosative stress, and preserving neuronal integrity. Despite their therapeutic potential, the pleiotropic and concentration-dependent actions of gasotransmitters pose substantial challenges for precise delivery and controlled bioavailability. However, donors or hybrid molecules, such as peptide conjugates, provide a suitable platform for sustained, controlled release of these gaseous molecules, overcoming their dose-dependent toxicity and facilitating protective biological effects. To date, the most advanced therapeutic strategies have focused on pharmacological inhibition of the NLRP3 inflammasome using synthetic compounds. Preclinical and emerging clinical studies demonstrate that such agents significantly modulate inflammasome-associated downstream signaling events through diverse molecular mechanisms. This review integrates current insights into NLRP3 inflammasome-driven pathology in age-associated neurodegenerative disorders, highlights the regulatory roles of endogenous gasotransmitters, and evaluates the therapeutic prospects of synthetic inflammasome-targeting agents for the treatment of neurodegenerative diseases in the aging population.
Arshi Waseem, Sudeshna Ghosh, M. Kumari et al.· Ageing Research Reviews· 0 citations
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ)-associated synaptic failure, intracellular Ca2+ dysregulation, and progressive impairment of lysosome-dependent clearance pathways. Aβ induces sustained Ca2+ overload, resulting in pathological hyperactivation of CaMKII, which normally participates in the regulation of autophagy. However, whether CaMKII hyperactivation contributes to Aβ-induced late-stage autophagy-lysosomal dysfunction and mitophagy failure remains unclear. This study aimed to examine the effects of the CaMKII inhibitor KN93 in Aβ25-35-exposed rat organotypic hippocampal slice cultures (OHSCs, ex vivo model) and the mouse brain in vivo. The results showed that Aβ25-35 induced intracellular Ca2+ elevation, CaMKII hyperactivation, and marked accumulation of LC3-II and p62. Ultrastructural and biochemical analyses revealed impaired lysosomal maturation, defective autophagosome-lysosome coupling, and accumulation of autophagic vacuoles, consistent with a blockade of late-stage autophagic flux. Increased levels of immature cathepsin D and reduced colocalization of LC3 with lysosomal markers further supported compromised lysosomal competence. Damaged mitochondria were recruited to lysosomal compartments but failed to undergo effective degradation, indicating abortive mitophagy under Aβ25-35 exposure. KN93 attenuated Aβ25-35-induced defects in lysosomal protease maturation, autophagosome-lysosome fusion, and mitochondrial clearance in both the ex vivo OHSCs model and the in vivo mouse brain. KN93 also ameliorated cognitive impairment in Aβ25-35-exposed mice. Taken together, these findings indicate that CaMKII hyperactivation contributes to Aβ25-35-induced autophagy-lysosomal dysfunction and neuronal damage, and that pharmacological inhibition of CaMKII with KN93 restores intracellular degradative capacity and ameliorates cognitive impairment under Aβ stress.
E. C. Suh, Yul A. Kim, K. Lee et al.· Neurochemistry International· 0 citations
Autoimmune uveitis is a vision-threatening inflammatory disorder driven by dysregulated T helper 17 (Th17) responses, yet therapeutic strategies targeting Th17 differentiation are lacking. Through transcriptomic screening of an experimental autoimmune uveitis (EAU) model and validation in peripheral blood mononuclear cells from Vogt-Koyanagi-Harada patients, we identified MAP1S (microtubule-associated protein 1S) as a pivotal, conserved regulator. Here, we demonstrate that MAP1S constrains pathogenic Th17 responses and alleviates EAU through a dual mechanism coordinating transcriptional control and autophagic degradation. Mechanistically, MAP1S binds to EGR2 (early growth response 2) and restrains its acetylation at Lys368, thereby suppressing Lcn2 (lipocalin 2) transcription. Besides, MAP1S facilitates autophagosome biogenesis and lysosomal trafficking, promoting the autophagic clearance of LCN2 protein. Notably, MAP1S deficiency enhances EGR2 acetylation, increases Lcn2 transcription, disrupts autophagosome trafficking, impairs LCN2 degradation, and promotes LCN2 accumulation, collectively driving Th17 polarization and exacerbating EAU pathology. Adoptive transfer of cervical lymph node cells from map1s knockout mice reproduced severe disease in wild-type recipients. Moreover, pharmacological activation of MAP1S with spermidine suppressed Th17 responses and alleviated disease severity. Our findings establish MAP1S as a critical node integrating acetylation signaling of EGR2 and autophagic flux to govern LCN2 homeostasis and Th17 pathogenicity, revealing a promising therapeutic target for autoimmune uveitis and potentially other Th17-mediated diseases.
Yingjun Cai, Li-Hui Xie, Bowen Li et al.· Autophagy· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
