Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity

• Published in: Neurobiology of disease Vol. 158; p. 105479
• Main Authors: Lemarié, Fanny L., Caron, Nicholas S., Sanders, Shaun S., Schmidt, Mandi E., Nguyen, Yen T.N., Ko, Seunghyun, Xu, Xiaohong, Pouladi, Mahmoud A., Martin, Dale D.O., Hayden, Michael R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2021; Elsevier
• Subjects: Acyl-protein thioesterase; Acyltransferases - genetics; Adaptor Proteins, Signal Transducing - genetics; Animals; Cell Line; Chlorocebus aethiops; COS Cells; Cysteine - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Humans; Huntingtin; Huntingtin Protein - genetics; Huntingtin Protein - toxicity; Huntington disease; Lipoylation - drug effects; Lipoylation - genetics; Lymphocytes - drug effects; Lymphocytes - metabolism; Male; Mice; Mutation; Nerve Tissue Proteins - genetics; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Palmitoylation; Rats; S-acylation; ZDHHC17; Neuroprotection; PAT; Huntingtin; ABE; Palmitoylation; APT; PalmB; Acyl-protein thioesterase; Huntington disease; hPSC; PTM; HTT; mHTT; HIP14; ZDHHC17; HAM; NEM; HD; HIP14L; S-acylation; ASO; ICV; LNA
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2021.105479

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulated. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that mHTT palmitoylation decreases further with aging. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons. •Palmitoylation of mHTT is reduced in multiple transgenic HD mouse models.•HTT palmitoylation decreases with increasing polyQ length in HD patient cells.•mHTT-lowering in mouse brains does not rescue aberrant palmitoylation.•mHTT palmitoylation in HD patient-derived cells can be rescued via APT inhibition.•Promoting palmitoylation reduces mHTT aggregation and cytotoxicity in vitro.