Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding for huntingtin protein. A lot has been learned about this disease since its first description in 1872 and the identification of its causative gene and mutation in 1993. We now know that the disease is characterized by several molecular and cellular abnormalities whose precise timing and relative roles in pathogenesis have yet to be understood. HD is triggered by the mutant protein, and both gain-of-function (of the mutant protein) and loss-of-function (of the normal protein) mechanisms are involved. Here we review the data that describe the emergence of the ancient huntingtin gene and of the polyglutamine trait during the last 800 million years of evolution. We focus on the known functions of wild-type huntingtin that are fundamental for the survival and functioning of the brain neurons that predominantly degenerate in HD. We summarize data indicating how the loss of these beneficial activities reduces the ability of these neurons to survive. We also review the different mechanisms by which the mutation in huntingtin causes toxicity. This may arise both from cell-autonomous processes and dysfunction of neuronal circuitries. We then focus on novel therapeutical targets and pathways and on the attractive option to counteract HD at its primary source, i.e., by blocking the production of the mutant protein. Strategies and technologies used to screen for candidate HD biomarkers and their potential application are presented. Furthermore, we discuss the opportunities offered by intracerebral cell transplantation and the likely need for these multiple routes into therapies to converge at some point as, ideally, one would wish to stop the disease process and, at the same time, possibly replace the damaged neurons.

Firefly luciferase mutants as sensors of proteome stress

“…Htt is also believed to play a role in vesicle transport and in regulating gene transcription and RNA trafficking (Cattaneo et al, 2005;Finkbeiner, 2011;Ross and Tabrizi, 2011;Zuccato et al, 2010). Therefore, HD involves both loss-of-function of the normal Htt that impairs its fundamental role in neuronal cells, and predominantly gain-of-function by the mutant Htt proteins that form amyloid-like inclusions ).…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…Another striking similarity between AD and HD is the presence of activated microglia as markers of inflammation 5,14 . Microglia produce quinolinic acid (QA), a selective NMDAR agonist and a metabolite of the tryptophan degradation pathway, that elicits symptoms reminiscent of HD when injected into the striatum, and symptoms similar to AD when injected into the nucleus basalis of rodents 35 .…”

“…Alterations in microglial tryptophan metabolism, leading to increased release of neurotoxic metabolites 5,14,35 Neurotrophic factor related abnormalities…”

“…There is evidence for the aberrant phosphorylation, palmitoylation and acetylation of disease-causing proteins, protein misfolding, failure to clear disease-causing proteins by the ubiquitin-proteasome system or autophagy, and changes in NMDA receptor activity at the synapse. Additional mechanisms include alterations in levels of brain-derived neurotrophic factor (BDNF) and neuronal growth factor (NGF) as well as associated receptors and trafficking pathways,, and increased activity of caspase enzymes in both disorders 5,6,9,14 (Table 1).…”

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

“…No disease-modifying treatment is available for HD and novel pathophysiological insights and therapeutic strategies are needed. 1 Lipids are vital to brain health and function. Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function.…”