Research: Huntington’s Disease


 

Huntington’s disease is an adult onset, autosomal dominant neurodegenerative disease that is clinically characterized by a triad of movement disorders (i.e., chorea and bradykinesia), psychiatric symptoms, and cognitive deficits. In afflicted patients, symptoms usually progress relentlessly until death 15-20 years after disease onset. HD affects about 1 in 10,000 people in US. Currently there are about 30,000 HD patients and another 150,000 people at risk.
HD is caused by a CAG repeat expansion encoding a polyglutamine (polyQ) repeat in huntingtin, a protein ubiquitously expressed in neurons as well as non-neuronal tissues. The polyQ repeat, located in the N-terminus of huntingtin normally has fewer than 36 glutamines, but is expanded to more than 40 in HD patients. Pathological hallmarks of HD include:

 

1. Atrophy (shrinkage) of the brain that is restricted to the cortex and striatum

2. Selective degeneration of the striatal medium spiny neurons, and to a lesser extent, to cortical pyramidal neurons

3. Aggregation of mutant htt in affected neurons (both in the nucleus as well as in neuronal processes)

 

The cellular and molecular mechanisms underlying the selective and progressive pathogenic processes in HD remain largely unclear, and there is currently no effective treatment or cure for HD. Our lab is interested in studying the cellular and molecular mechanisms underlying pathogenesis of Huntington’s disease by using conditional genetics to identify important cells and circuits for HD pathology, and by assessing the molecular changes in those critical regions that contribute to cellular dysfunction and toxicity. HD research in the lab approaches HD research from two directions:

 

Defining Neuronal Targets in Huntington’s Disease Pathogenesis Using Mouse Models of HD. Researchers in the lab previously used conditional mouse models with Cre-dependent expression of a pathogenic mutant Huntingtin (mHTT) exon 1 fragment to show that toxic mHTT fragments can elicit pathological cell-cell interactions that contribute to cortical and striatal pathogenesis. Further work in the lab led to the development of the first conditional bacteria artificial chromosome (BAC) transgenic mouse model of HD (BACHD), which expresses full-length human mHTT with human genomic regulation. BACHD mice exhibit progressive behavioral and neuropathological phenotypes and are used worldwide for both mechanistic and therapeutic studies. Using this pioneering conditional BAC transgenic HD mouse, the Yang lab systematically switched-off expression of mHTT in cortical neurons, striatal neurons or both, and were able to demonstrate distinct and synergistic roles of mHTT in both cortical and striatal neurons in disease pathogenesis. The key findings in this study include the critical roles of cortical mHTT in disease pathogenesis (e.g. eliciting psychiatric-like behavioral deficits and non-cell-autonomously triggering striatal synaptic toxicities), as well as demonstrating the importance of reducing mHTT in both cortical and striatal neurons for ameliorating disease phenotypes in this model. These studies are highly informative for clinical trials involving the delivery of HTT-lowering therapies (e.g. antisense oligonucleotides or RNA interference) into HD patient brains.

 

Validating Molecular Mechanisms and Therapeutic Targets for Huntington’s Disease. The Yang lab has applied mouse genetics to validate several molecular pathogenic mechanisms and targets for HD. The lab used transgenic HD mice with phosphomimetic and phosphoresistant mutations at serines 13 and 16 to show that these residues can act as a molecular switch to suppress mHTT-induced pathogenesis in vivo. Researchers in the lab recently developed BAC HD mice that express mHTT that lacks a functional N17 domain, demonstrating that this domain is critical in suppressing mHTT nuclear pathogenesis. This new model of HD exhibits accelerated nuclear pathogenesis and striking, novel HD-like movement deficits, progressive neurological decline, weight loss, and robust striatal neuron loss with neuroinflammation. This is the first HD mouse model to capture many features of clinically manifest HD. These two studies have demonstrated the critical roles of N17 as a bi-directional molecular switch that can modify HD pathogenesis in vivo.

 

A major lab accomplishment was the discovery that reduction of ATM signaling can ameliorate mHTT toxicities in cell and animal models of HD. ATM is a kinase involved in multiple signaling pathways, and is best known for its function in orchestrating DNA damage repair and activation of apoptosis. Researchers in the lab found elevated ATM signaling in HD cell and mouse models, and also in postmortem patient brains. We also found critical evidence that deleting one copy of the Atm gene in mice and in Drosophila results in amelioration of behavioral deficits and partially improves neuropathology. Further, small molecule ATM inhibitors were beneficial in rodent and patient iPSC models of HD. This study represents the validation of partial ATM inhibition as novel therapeutic strategy for HD, and small molecular inhibitors of ATM are now being pursued for HD therapeutics.

 

Additionally, our laboratory has been taking systems biology approach to understand the molecular networks through which mHTT elicit cortical and striatal pathogenesis and to find new molecular targets. We published the first in vivo full-length HTT interactome, consisting of 750 interactors, in the mouse brain. We also were the first group to apply Weighted Gene Correlation Network Analyses (WGCNA) to proteomic interactome data to define the endogenous htt interacting network in the mammalian brain. This approach has also been used to find gene networks that are perturbed in our HD mouse models.

 


 

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