Huntington’s Disease

Huntington’s Disease (HD) is a devastating neurodegenerative disease that has as its primary genetic cause a mutation in the huntingtin (htt) protein. Expansion of a CAG repeat in the htt gene results in a “gain of toxicity” that leads to neuronal cell death via as yet poorly understood mechanisms. Much or most of the toxicity is due to misfolded forms of the mutant htt protein that features an expanded polyglutamine (polyQ) segment. The misfolded protein self-assembles into differently structured protein assemblies that are suggested to either enhance cellular toxicity (e.g. by sequestering vital polyQ-containing proteins [2]), or act as a “safety mechanism” that removes other, toxic species of mutant htt and its fragments.

In a NIH-funded project, we are using ssNMR spectroscopy to elucidate the conformation of the protein fibrils. In 2011 we reported the first use of ssNMR on fibrils of polyQ and huntingtin N-terminal fragments (HNTF) [5]. In several publications [1-6], we have shown that htt exon1 and other polyQ aggregates share a similarly structured polyQ amyloid core. We showed that the polyQ core of aggregated htt exon1 contains a β-hairpin structure[6], whose formation is a pivotal step in the protein aggregation process [3]. The htt domains flanking polyQ have dramatic effects on the misfolding and aggregation behavior, but are not incorporated into this amyloid core [1,4,5]. Instead,the N-terminal segment (httNT, or N17) features an α-helix that is solvent-exposed [1,5]. The (possibly protective) proline rich domain ends up in a PPII helices. We are continuing our studies of the misfolded protein aggregates to determine how chaperones, antibodies and other htt-binding proteins can be used to modulate the disease-causing misfolding and aggregation process.

A neurodegenerative mechanism in HD that occurs downstream of the misfolding and self-assembly of mutant htt involves mitochondrial dysfunction and apoptosis. An up regulation of apoptosis is responsible for neuronal death. We have an ongoing NIH-funded project studying pivotal cardiolipin-cytochrome-c interactions that play a critical (and potentially druggable) role in this toxic mechanism.

Related publications from the Van der Wel lab

[1] Hoop, C. L., et al. (2014) Polyglutamine amyloid core boundaries and flanking domain dynamics in huntingtin fragment fibrils determined by solid-state NMR, Biochemistry, 53(42): 6653-6666. Full-text
[2] Kar, K., et al. (2014) D-polyglutamine amyloid recruits L-polyglutamine monomers and kills cells, J Mol Biol 426, 816-829. Here
[3] Kar, K., et al. (2013) β-hairpin-mediated nucleation of polyglutamine amyloid formation, J Mol Biol 425, 1183–1197. Full text
[4] Mishra, R., et al. (2012) Serine Phosphorylation Suppresses Huntingtin Amyloid Accumulation by Altering Protein Aggregation Properties, J Mol Biol 424, 1-14. Here
[5] Sivanandam, V. N., et al. (2011) The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils, J Am Chem Soc 133, 4558-4566.
[6] Hoop et al. (2016)  Huntingtin exon 1 fibrils feature an interdigitated β-hairpin-based polyglutamine core. Proc Natl Acad Sci USA 113(6): 1546-1551
[7] Lin et al. (2017) Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core. Nature Commum.

 

Related internet resources: