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Publications of the Week

Rescue of Aberrant Huntingtin Palmitoylation Ameliorates Mutant Huntingtin-Induced Toxicity

By September 8, 2021September 13th, 2021No Comments

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This week we profile a recent publication in Neurobiology of Disease from the lab of Dr. Michael Hayden (pictured, right)
at the Centre for Molecular Medicine and Therapeutics with first author Dr. Fanny Lemarié (left).

Can you provide a brief overview of your lab’s current research focus?

Our lab studies Huntington disease which is an inherited neurodegenerative disorder that affects 1 in 7,500 individuals in the Western world. It is characterized by involuntary movements, cognitive disorders including dementia, eventually leading to death. The cause of Huntington disease is a mutation in the HTT gene, which produces the toxic mutant huntingtin protein. 

My team aims at developing therapeutics to reduce the protein level and the toxicity of mutant huntingtin in the brain.

One of the strategies presented in this publication consists of modulating the level of a post-transcriptional modification of mutant huntingtin, called palmitoylation (the addition of a palmitic acid onto a protein). Palmitoylation plays an important role in neurodevelopmental processes and neuronal survival.

What is the significance of the findings in this publication?

In this publication, we find that palmitoylation of mutant huntingtin is decreased in multiple Huntington disease mouse models and patient cells, and that mutant huntingtin palmitoylation decreases further with aging.

We demonstrate that mutant huntingtin palmitoylation can be enhanced in vitro using an inhibitor of the acyl-protein thioesterase (APT) depalmitoylation enzyme, which catalyzes the removal of palmitic acid from proteins. Moreover, we show that increasing palmitoylation reduces mutant huntingtin aggregation and mutant huntingtin-induced cytotoxicity in vitro.

Further studies evaluating the impact of promoting palmitoylation, on well-characterized Huntington disease phenotypes will help elucidate the potential mechanism of action leading to the observed protective effects.

What are the next steps for this research?

We will test different strategies to modulate mutant huntingtin palmitoylation level in vivo to evaluate their therapeutic potential.

If you’d like to mention your funding sources, please list them.

We would like to thank the CIHR and the CHDI foundations for funding this work.


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