Hayden Lab Research Projects

Huntington Disease (HD) is a devastating incurable neurodegenerative disease that affects about 5,000 Canadians. Inheriting a single mutant copy of the Huntingtin (HTT) gene from either parent is sufficient to cause HD. The mutated HTT gene codes for production of the toxic, mutant huntingtin protein (mHTT) that is responsible for killing brain cells in HD. Importantly, the other, non-mutated (or normal) copy of the huntingtin protein is critical for the health of brain cells. Consequently, our research goals are to reduce mHTT through multipronged approaches that specifically target the mutant gene and also develop approaches to enhance the clearance of mutant protein.

My current research projects include:

Silencing the gene that causes Huntington disease– Mutant huntingtin protein is the cause of Huntington disease (HD) and engages in a variety of aberrant interactions in neurons. Preventing generation of this toxic protein by gene silencing, the process of switching off a gene, should prevent all subsequent pathology and prevent or delay the onset of HD. Everyone has two copies of the huntingtin gene. In HD, one of these copies carries the mutation while the other copy is normal. The normal huntingtin protein is important for maintaining neuronal health and long-term reduction of this protein may not be well-tolerated. We are developing a strategy of silencing only the mutant copy of a patient’s huntingtin gene using antisense oligonucleotides targeted to HD mutation-associated single nucleotide variants as a treatment for HD.

Modulating mHTT post-translational modifications (PTMs) to enhance its clearance – Huntingtin (HTT) undergoes a myriad of post-translational modifications (PTMs) including phosphorylation, proteolytic cleavages and fatty acylation that influence the protein function, localization and clearance. Those PTMs are essential for neuronal viability, but are altered in HD. We have shown that promoting or preventing specific HTT PTMs can either dramatically improve or exacerbate HD symptoms. There is also evidence that HTT PTMs work in concert and may regulate one another. However, the interactions between the networks of HTT PTMs remain mostly unstudied. Our objectives are therefore to identify new rate-limiting PTMs, characterize the interrelationship of the HTT PTM network in vivo and understand how it relates to HTT function, stability and clearance. This project will allow us to determine and validate molecular targets for therapeutic strategies that could be used in synergy with HTT gene silencing.

Discovery of novel therapeutic targets for neuroprotection in Huntington Disease – Glutamate excitotoxicity and mitochondrial dysfunction are critical, closely-linked pathogenic mechanisms in several acute and neurodegenerative brain disorders, including HD. Together, these processes contribute to altered intracellular calcium dynamics, bioenergetic defects, cell death signaling, and synaptic instability. We are investigating novel therapeutic targets involved in these pathways with the goal of improving mitochondrial health and normalizing synaptic function in HD.

Population genetics and epidemiology of the Huntington disease mutation – The HD mutation is associated with specific sets of genetic variants in the surrounding HTT gene, known as haplotypes. We are performing detailed investigations of haplotypes HD mutation in different populations around the world. Haplotypes of the HD mutation allow for identification of new targets for therapeutic gene silencing and offer insight into the origin of the HD mutation in different ethnic groups. We additionally study how many people have the HD mutation, how often this mutation results in HD symptoms, and how often unstable new mutations for HD occur in the general population.