IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.

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.Abbreviations: 3-MA; 3-methyladenine; Aβ, amyloid beta; AIF1/Iba1, allograft inflammatory factor 1; ALP, autophagy-lysosomal pathway; ALR, autophagic lysosomal reformation; ATG7, autophagy related 7; ATG5, autophagy related 5; Baf A1, bafilomycin A1; BBB, blood-brain barrier; BDNF, brain derived neurotrophic factor; CSF, cerebrospinal fluid; CTSB, cathepsin B; CTSD, cathepsin D; DLG4/PSD-95, discs large MAGUK scaffold protein 4; GFAP, glial fibrillary acidic protein; GSK3B/GSK-3β, glycogen synthase kinase 3 beta; HD, Huntington disease; HTT, huntingtin; ICV, intracerebroventricular; IL17A, interleukin 17A; IL17A mAb, IL17A monoclonal antibody; IL17RA, interleukin 17 receptor A; IV, intravenous; LAMP2, lysosomal-associated membrane protein 2; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; mHTT, mutant HTT; RBFOX3/NeuN, RNS binding protein, fox-1 homolog (C. elegans) 3; p-CREB1/CREB, phospho-cAMP responsive element binding protein 1; PIP5K1A, phosphatidylinositol-4-phosphate 5-kinase, type 1 alpha; PPP1R1B/DARPP-32, protein phosphatase 1 regulatory inhibitor subunit 1B; rIL17A, recombinant IL17A; SQS, self-quenched substrate; SQSTM1/p62, sequestosome 1; MAPT/tau, microtubule-associated protein tau; TDG, tideglusib; TFE3, transcript factor E3; TFEB, transcript factor EB; Th17, T helper 17; TX-100, Triton X-100; WT, wild-type.