https://www.linkgroup.hu/docs/13PharmTher.pdf

Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review

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.

Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease

https://sites.duke.edu/eroglulab/files/2015/02/2-Eroglu_2009_Cell.pdf

Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis

The Biology of Huntingtin

Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.

/pdf/mutant-huntingtin-binds-the-mitochondrial-fission-gtpase-3ftc2ciry4.pdf

Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity

Huntington's disease (HD) is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt) protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%–4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to co-immunoprecipitate with full-length Htt from mouse brain. These studies demonstrate that high-throughput screening for protein interactions combined with genetic validation in a model organism is a powerful approach for identifying novel candidate modifiers of polyglutamine toxicity.

/pdf/huntingtin-interacting-proteins-are-genetic-modifiers-of-3dkhcpf5n2.pdf

Anthony Hurlburt

Papers

Huntingtin interacting proteins are genetic modifiers of neurodegeneration.