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Discovery of an autophagy inducer J3 to lower mutant huntingtin and alleviate Huntington's disease-related phenotype.

Cell & bioscience (2022-10-09)
Jiahui Long, Xia Luo, Dongmei Fang, Haikun Song, Weibin Fang, Hao Shan, Peiqing Liu, Boxun Lu, Xiao-Ming Yin, Liang Hong, Min Li
RESUMEN

Huntington's disease (HD) is a neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein encoded from extra tracts of CAG repeats in exon 1 of the HTT gene. mHTT proteins are neurotoxic to render the death of neurons and a series of disease-associated phenotypes. The mHTT is degraded through autophagy pathway and ubiquitin-proteasome system (UPS). This study identified a small molecule, J3, as an autophagy inducer by high-content screening. The results revealed that J3 could inhibit mTOR, thus promoting autophagic flux and long-lived protein degradation. Further, J3 selectively lowered the soluble and insoluble mHTT but not wild type HTT levels in cell models. The HdhQ140 mice showed reduced HD-associated activity and loss of motor functions. However, administration of J3 showed increased activity and a slight improvement in the motor function in the open-field test, balance beam test, and rotarod tests. Furthermore, in vivo studies revealed that J3 decreased T-HTT and misfolded protein levels in the striatum and increased the levels of the medium spiny neuron marker DARPP-32. In addition, J3 showed good permeability across the brain-blood barrier efficiently, suggesting that J3 was a promising candidate for the treatment of HD.

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Sigma-Aldrich
Anti-LC3B antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution