Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity

Abstract

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 posttranslational 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 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 humanized 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 modulated by pharmacological intervention. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that aging further reduces HTT palmitoylation. 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.

Glia: A major player in glutamate–GABA dysregulation‐mediated neurodegeneration

“…The selective palmitoylation and depalmitoylation are catalyzed by enzymes zDHHC (Aspartate‐Histidine‐Histidine‐Cysteine) protein acyltransferase/palmitoyltransferase and acyl‐protein thioesterases, respectively, which can act as potential targets. There was no such molecule to alter the palmitoylation status of the target protein until recently, when mHTT palmitoylation was normalized using an acyl‐protein thioesterase (APT) inhibitor in COS‐7 cells, in YAC128 corticostriatal primary neurons, and HD patient‐derived lymphoblasts (Lemarié et al, 2021). However, the latter have not discussed about the EAAT palmitoylation status.…”

A sticky situation: regulation and function of protein palmitoylation with a spotlight on the axon and axon initial segment

“…HD is a neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene coding for an elongated polyglutamine tract in the huntingtin (HTT) protein (122). HTT is normally palmitoylated at Cys214 by ZDHHC17 and ZDHHC13 (also known as Huntingtin Interacting Proteins [HIP] 14 and 14-like [HIP14 and HIP14L], respectively) (3,123) but mutant HTT is less palmitoylated in HD patient derived cells and mouse models of HD (123,124). Recent exciting findings from the Hayden and Saudou groups show that increasing palmitoylation by inhibiting the HTT depalmitoylating enzymes in cellulo and in vivo reduces cytotoxicity, mutant HTT aggregation, and restores trafficking deficits in cell culture and rescues behaviour and neuropathology in HD mice (124,125).…”

“…HTT is normally palmitoylated at Cys214 by ZDHHC17 and ZDHHC13 (also known as Huntingtin Interacting Proteins [HIP] 14 and 14-like [HIP14 and HIP14L], respectively) (3,123) but mutant HTT is less palmitoylated in HD patient derived cells and mouse models of HD (123,124). Recent exciting findings from the Hayden and Saudou groups show that increasing palmitoylation by inhibiting the HTT depalmitoylating enzymes in cellulo and in vivo reduces cytotoxicity, mutant HTT aggregation, and restores trafficking deficits in cell culture and rescues behaviour and neuropathology in HD mice (124,125). These two studies provide strong evidence for a role of palmitoylation in HD and rationale for targeting depalmitoylating enzymes to treat HD.…”