Campbell HD et al. (1993) Proc Natl Acad Sci U S A "The Drosophila melanogaster flightless-I gene involved in gastrulation and muscle degeneration encodes gelsolin-like and leucine-rich repeat domains and is conserved in Caenorhabditis elegans and humans."

Campbell HD, Kasprzak AB, Ozsarac N, Cotsell JN, Miklos GLG, Claudianos C, Schimansky T, Young IG, de Couet HG

[Proc Natl Acad Sci U S A, 1993]

Mutations at the flightless-I locus (fliI) of Drosophila melanogaster cause flightlessness or, when severe, incomplete cellularization during early embryogenesis, with subsequent abnormalities in mesoderm invagination and in gastrulation. After chromosome walking, deficiency mapping, and transgenic analysis, we have isolated and characterized flightless-I cDNAs, enabling prediction of the complete amino acid sequence of the 1256-residue protein. Data base searches revealed a homologous gene in Caenorhabditis elegans, and we have isolated and characterized corresponding cDNAs. By using the polymerase chain reaction with nested sets of degenerate oligonucleotide primers based on conserved regions of the C. elegans and D. melanogaster proteins, we have cloned a homologous human cDNA. The predicted C. elegans and human proteins are, respectively, 49and 58-134223489dentical to the D. melanogaster protein. The predicted proteins have significant sequence similarity to the actin-binding protein gelsolin and related proteins and, in addition, have an N-terminal domain consisting of a repetitive amphipathic leucine-rich motif. This repeat is found in D. melanogaster, Saccharomyces cerevisiae, and mammalian proteins known to be involved in cell adhesion and in binding to other proteins. The structure of the maternally expressed flightless-I protein suggests that it may play a key role in embryonic cellularization by interacting with both the cytoskeleton and other cellular components. The presence of a highly conserved homologue in nematodes, flies, and humans is indicative of a fundamental role for this protein in many metazoans.

Varma H et al. (2007) Nat Chem Biol "Selective inhibitors of death in mutant huntingtin cells."

DeMarco CT, Voisine C, Stockwell BR, Varma H, Cattaneo E, Lo DC, Hart AC

[Nat Chem Biol, 2007]

Huntington disease (HD) is an inherited neurodegenerative disorder with unclear pathophysiology. We developed a high-throughput assay in a neuronal cell culture model of HD, screened 43,685 compounds and identified 29 novel selective inhibitors of cell death in mutant huntingtin-expressing cells. Four compounds were active in diverse HD models, which suggests a role for cell death in HD; these compounds are mechanistic probes and potential drug leads for HD.

Dorsman JC et al. (1998) Worm Breeder's Gazette "Phenotypical and biochemical analysis of C. elegans carrying the human Huntington disease gene."

den Dunnen JT, van Luenen HGAM, Plasterk RHA, Van Ommen GJB, Smoor MA, Bout M, Dorsman JC

[Worm Breeder's Gazette, 1998]

Huntington's disease (HD) is a neurodegenerative CAG (gln) repeat expansion disorder with a mid-life onset. Animal models may assist in the understanding of the molecular pathology of HD and other neurodegenerative diseases caused by similar repeat expansions. In mice an expanded CAG repeat in exon 1 of the HD gene is sufficient to cause a progressive neurological phenotype. Thus far no HD homolog has been identified in C. elegans.

Machiela E et al. (2016) Neurobiol Dis "Oxidative stress is increased in C. elegans models of Huntington's disease but does not contribute to polyglutamine toxicity phenotypes."

Dues DJ, Van Raamsdonk JM, Machiela E, Senchuk MM

[Neurobiol Dis, 2016]

Huntington's disease (HD) is an adult onset neurodegenerative disorder for which there is currently no cure. While HD patients and animal models of the disease exhibit increased oxidative damage, it is currently uncertain to what extent oxidative stress contributes to disease pathogenesis. In this work, we use a genetic approach to define the role of oxidative stress in HD. We find that a C. elegans model of HD expressing a disease-length polyglutamine tract in the body wall muscle is hypersensitive to oxidative stress and shows an upregulation of antioxidant defense genes, indicating that the HD worm model has increased levels of oxidative stress. To determine whether this increase in oxidative stress contributes to the development of polyglutamine-toxicity phenotypes in this HD model, we examined the effect of deleting individual superoxide dismutase (sod) genes in the HD worm model. As predicted, we found that deletion of sod genes in the HD worm model resulted in a clear increase in sensitivity to oxidative stress. However, we found that increasing oxidative stress in the HD worm model did not exacerbate deficits caused by polyglutamine toxicity. We confirmed these observations in two worm models expressing disease-length polyglutamine tracts in neurons. Furthermore, we found that treatment antioxidants failed to rescue movement deficits or decrease aggregation in HD worm models. Combined, this suggests that the increase in oxidative stress in worm models of HD does not contribute to the phenotypic deficits observed in these worms, and provides a possible explanation for the failure of antioxidants in HD clinical trials.

Cong W et al. (2019) ACS Appl Mater Interfaces "Selenium Nanoparticles as an Efficient Nanomedicine for the Therapy of Huntington's Disease."

Wang L, Bai R, Chen C, Li YF, Cong W

[ACS Appl Mater Interfaces, 2019]

Huntington's disease (HD) is an incurable disease with progressive loss of neural function, which is influenced by epigenetic, oxidative stress, metabolic, and nutritional factors. Targeting inhibition of huntingtin protein aggregation is a strategy for HD therapy, but the efficacy is unsatisfactory. Studies found that selenium (Se) levels in the brain is insufficient for HD disease, while improvement in Se homeostasis in the brain may attenuate neuronal loss and dysfunction. In this study, we applied selenium nanoparticles (NPs) (Nano-Se) for the HD disease therapy by regulating HD-related neurodegeneration and cognitive decline based on transgenic HD models of Caenorhabditis elegans (C. elegans). At low dosages, Nano-Se NPs significantly reduced neuronal death, relieved behavioral dysfunction, and protected C. elegans from damages in stress conditions. Molecular mechanism also revealed that Nano-Se attenuated oxidative stress, inhibited the aggregation of huntingtin proteins, and down regulated the expression of histone deacetylase family members at mRNA levels. The results suggested that Nano-Se has great potential for Huntington's disease therapy. In conclusion, mechanism about how Nano-Se NPs protect from damages in stress conditions and repair neural functions will benefit to HD disease therapy. This study will also guide rational design of Nano-Se NPs or other selenium compounds to improve HD therapy in the future.

Winnier AR et al. (1997) International C. elegans Meeting "RESIDUES OUTSIDE OF THE HOMEODOMAIN ARE REQUIRED FOR UNC-4 FUNCTION"

Miller DM, Saito T, Winnier AR

[International C. elegans Meeting, 1997]

Homeodomain (HD) proteins function as DNA-specific regulators of gene expression. The gene regulatory function of the HD can be augmented by sequences outside of this domain (i.e. paired, LIM, POU). We have identified residues outside of the UNC-4 HD that are required for its function: specifying synaptic input to VA motor neurons. A cluster of five missense mutations were identified C-terminal to the HD. These residues are contained within a region predicted to form four beta sheets separated by turns (BTB). We note that specific BTB mutations are suppressed by a specific missense mutation in unc-37, a groucho-like transcription factor. Therefore, one function of the BTB domain may be to mediate UNC-4/UNC-37 interactions. The vertebrate HD proteins PHD1 and uncx-4.1 share 90% identity with the UNC-4 HD but do not include an UNC-4-like BTB domain. We evaluated the ability of a vertebrate UNC-4-like HD to substitute for unc-4 function. The rat HD protein, PHD1,under unc-4 promoter control, fails to rescue unc-4(wd1) animals, suggesting that both BTB and HD residues are required to regulate synaptic specificity in C. elegans. To identify additional unc-4-interacting genes, we are performing screens for dominant suppressors of BTB mutations. One novel suppressor mutation has been identified. bkn-1(wd29) (backing again) maps to the 0.5 m.u. interval between bli-6 and unc-24 (IV). Like unc-37(gf), wd29 suppresses specific missense mutations in the BTB domain as well as in the HD. This allele-specific suppression suggests that wd29 may affect the activity of a transcription factor that functions with unc-4.

Rubinsztein DC (2002) Trends Genet "Lessons from animal models of Huntington's disease."

Rubinsztein DC

[Trends Genet, 2002]

Huntington''s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product, huntingtin. Studies in mouse models and human suggest that the mutation is associated with a deleterious gain of function. There is now a wide range of mouse models for HD, providing important insights into processes associated with disease pathogenesis. These models have been complemented by studies in Drosophila and Caenorhabditis elegans that have allowed the identification of possible modifier loci through suppressor screens.

Lejeune F et al. (2012) BMC Genomics "Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons."

Vazquez R, Tourette C, Bicep C, Mesrob L, Neri C, Parker A, Lejeune F, Parmentier F, Vert JP

[BMC Genomics, 2012]

BACKGROUND: A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. RESULTS: Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified. CONCLUSIONS: Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD.

Koyuncu S et al. (2018) Nat Commun "The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington's disease patients."

Hoppe T, Lee HJ, Pokrzywa W, Koyuncu S, Fatima A, Gutierrez-Garcia R, Vilchez D, Saez I

[Nat Commun, 2018]

Induced pluripotent stem cells (iPSCs) undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome. As such, iPSCs suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington's disease (HD). Here we show that proteasome activity determines HTT levels, preventing polyQ-expanded aggregation in iPSCs from HD patients (HD-iPSCs). iPSCs exhibit high levels of UBR5, a ubiquitin ligase required for proteasomal degradation of both normal and mutant HTT. Conversely, loss of UBR5 increases HTT levels and triggers polyQ-expanded aggregation in HD-iPSCs. Moreover, UBR5 knockdown hastens polyQ-expanded aggregation and neurotoxicity in invertebrate models. Notably, UBR5 overexpression induces polyubiquitination and degradation of mutant HTT, reducing polyQ-expanded aggregates in HD-cell models. Besides HTT levels, intrinsic enhanced UBR5 expression determines global proteostasis of iPSCs preventing the aggregation of misfolded proteins ensued from normal metabolism. Thus, our findings indicate UBR5 as a modulator of super-vigilant proteostasis of iPSCs.

Vela M et al. (2021) ACS Chem Neurosci "Neuroprotective Effect of IND1316, an Indole-Based AMPK Activator, in Animal Models of Huntington Disease."

Castro A, Sanz P, Bono-Yague J, Garcia-Gimeno MA, Vela M, Priego EM, Vazquez-Manrique RP, Campos A, Lagartera L, Sanchis A, Cumella J, Perez C

[ACS Chem Neurosci, 2021]

Aggregation of mutant huntingtin, because of an expanded polyglutamine track, underlies the cause of neurodegeneration in Huntington disease (HD). However, it remains unclear how some alterations at the cellular level lead to specific structural changes in HD brains. In this context, the neuroprotective effect of the activation of AMP-activated protein kinase (AMPK) appears to be a determinant factor in several neurodegenerative diseases, including HD. In the present work, we describe a series of indole-derived compounds able to activate AMPK at the cellular level. By using animal models of HD (both worms and mice), we demonstrate the in vivo efficacy of one of these compounds (IND1316), confirming that it can reduce the neuropathological symptoms of this disease. Taken together, in vivo results and in silico studies of druggability, allow us to suggest that IND1316 could be considered as a promising new lead compound for the treatment of HD and other central nervous system diseases in which the activation of AMPK results in neuroprotection.