scholarly journals Nuclease-Deficient FEN-1 Blocks Rad51/BRCA1-Mediated Repair and Causes Trinucleotide Repeat Instability

2003 ◽  
Vol 23 (17) ◽  
pp. 6063-6074 ◽  
Author(s):  
Craig Spiro ◽  
Cynthia T. McMurray
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mammalian Cells ◽  
Direct Evidence ◽  
Trinucleotide Repeat ◽  
Human Cells ◽  
Wild Type ◽  
Repeat Instability ◽  
In Cells

ABSTRACT Previous studies have shown that expansion-prone repeats form structures that inhibit human flap endonuclease (FEN-1). We report here that faulty processing by FEN-1 initiates repeat instability in mammalian cells. Disease-length CAG tracts in Huntington's disease mice heterozygous for FEN-1 display a tendency toward expansions over contractions during intergenerational inheritance compared to those in homozygous wild-type mice. Further, with regard to human cells expressing a nuclease-defective FEN-1, we provide direct evidence that an unprocessed FEN-1 substrate is a precursor to instability. In cells with no endogenous defects in DNA repair, exogenous nuclease-defective FEN-1 causes repeat instability and aberrant DNA repair. Inefficient flap processing blocks the formation of Rad51/BRCA1 complexes but invokes repair by other pathways.

C01 Trinucleotide repeat instability in Huntington's disease

2010 ◽  
Vol 81 (Suppl 1) ◽  
pp. A16.1-A16
Author(s):  
B A Pepers ◽  
J T den Dunnen ◽  
G-J B van Ommen ◽  
W M C van Roon-Mom
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Repeat Instability

Huntington's disease: from pathology and genetics to potential therapies

2008 ◽  
Vol 412 (2) ◽  
pp. 191-209 ◽  
Author(s):  
Sara Imarisio ◽  
Jenny Carmichael ◽  
Viktor Korolchuk ◽  
Chien-Wen Chen ◽  
Shinji Saiki ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Mutant Protein ◽  
Mutant Huntingtin ◽  
Genetic Screens ◽  
Wild Type ◽  
Biological Studies ◽  
Polyglutamine Tract

Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion encoding an abnormally long polyglutamine tract in the huntingtin protein. Much has been learnt since the mutation was identified in 1993. We review the functions of wild-type huntingtin. Mutant huntingtin may cause toxicity via a range of different mechanisms. The primary consequence of the mutation is to confer a toxic gain of function on the mutant protein and this may be modified by certain normal activities that are impaired by the mutation. It is likely that the toxicity of mutant huntingtin is revealed after a series of cleavage events leading to the production of N-terminal huntingtin fragment(s) containing the expanded polyglutamine tract. Although aggregation of the mutant protein is a hallmark of the disease, the role of aggregation is complex and the arguments for protective roles of inclusions are discussed. Mutant huntingtin may mediate some of its toxicity in the nucleus by perturbing specific transcriptional pathways. HD may also inhibit mitochondrial function and proteasome activity. Importantly, not all of the effects of mutant huntingtin may be cell-autonomous, and it is possible that abnormalities in neighbouring neurons and glia may also have an impact on connected cells. It is likely that there is still much to learn about mutant huntingtin toxicity, and important insights have already come and may still come from chemical and genetic screens. Importantly, basic biological studies in HD have led to numerous potential therapeutic strategies.

scholarly journals TBK1 regulates autophagic clearance of soluble mutant huntingtin and inhibits aggregation/toxicity in different models of Huntington’s disease

2019 ◽  
Author(s):  
Ramanath Narayana Hegde ◽  
Anass Chiki ◽  
Lara Petricca ◽  
Paola Martufi ◽  
Nicolas Arbez ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mammalian Cells ◽  
Neuronal Cultures ◽  
Autophagic Flux ◽  
Primary Neurons ◽  
Wild Type ◽  
Neuroprotective Effects ◽  
Dependent Inhibition

AbstractPhosphorylation of the N-terminal domain of the Huntingtin (HTT) protein (at T3, S13, and S16) has emerged as a key regulator of HTT stability, clearance, localization, aggregation and toxicity. Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that specifically and efficiently phosphorylates both wild-type and mutant full-length or N-terminal fragments of HTT in vitro (S13/S16) and in cell/ neuronal cultures (S13). We show that overexpression of TBK1 in mammalian cells, primary neurons and a Caenorhabditis elegans model of Huntington’s Disease (HD) increases mutant HTTex1 phosphorylation, lowers its levels, increases its nuclear localization and significantly reduces its aggregation and cytotoxicity. Our mechanistic studies demonstrate that the TBK1-mediated neuroprotective effects are due to phosphorylation-dependent inhibition of mutant HTTex1 aggregation and an increase in autophagic flux. These findings suggest that upregulation and/or activation of TBK1 represents a viable strategy for the treatment of HD.Graphical abstract

scholarly journals Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes

2009 ◽  
Vol 33 (1) ◽  
pp. 37-47 ◽  
Author(s):  
Ella Dragileva ◽  
Audrey Hendricks ◽  
Allison Teed ◽  
Tammy Gillis ◽  
Edith T. Lopez ◽  
...  
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Dna Repair Genes ◽  
Repeat Instability ◽  
Repair Genes

scholarly journals Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex

2021 ◽  
pp. 1-13
Author(s):  
Karen A. Sap ◽  
Arzu Tugce Guler ◽  
Aleksandra Bury ◽  
Dick Dekkers ◽  
Jeroen A.A. Demmers ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Cortex ◽  
Full Length ◽  
Biological Processes ◽  
Interacting Proteins ◽  
Mutant Huntingtin ◽  
Wild Type ◽  
Mutant Huntingtin Protein ◽  
Mice Brain

Background: Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein. Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology. Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS). Results: We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2. Conclusion: Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology.

scholarly journals Special Issue: DNA Repair and Somatic Repeat Expansion in Huntington’s Disease

2021 ◽  
Vol 10 (1) ◽  
pp. 3-5
Author(s):  
Lesley Jones ◽  
Vanessa C. Wheeler ◽  
Christopher E. Pearson
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Expansion ◽  
Special Issue

Abnormal Spinal Cord Myelination due to Oligodendrocyte Dysfunction in a Model of Huntington’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Costanza Ferrari Bardile ◽  
Harwin Sidik ◽  
Reynard Quek ◽  
Nur Amirah Binte Mohammad Yusof ◽  
Marta Garcia-Miralles ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Oligodendrocyte Progenitor Cells ◽  
Wild Type ◽  
Specific Expression ◽  
Relative Contribution ◽  
Related Proteins ◽  
The Impact ◽  
Cervical Area

Background: The relative contribution of grey matter (GM) and white matter (WM) degeneration to the progressive brain atrophy in Huntington’s disease (HD) has been well studied. The pathology of the spinal cord in HD is comparatively less well documented. Objective: We aim to characterize spinal cord WM abnormalities in a mouse model of HD and evaluate whether selective removal of mutant huntingtin (mHTT) from oligodendroglia rescues these deficits. Methods: Histological assessments were used to determine the area of GM and WM in the spinal cord of 12-month-old BACHD mice, while electron microscopy was used to analyze myelin fibers in the cervical area of the spinal cord. To investigate the impact of inactivation of mHTT in oligodendroglia on these measures, we used the previously described BACHDxNG2Cre mouse line where mHTT is specifically reduced in oligodendrocyte progenitor cells. Results: We show that spinal GM and WM areas are significantly atrophied in HD mice compared to wild-type controls. We further demonstrate that specific reduction of mHTT in oligodendroglial cells rescues the atrophy of spinal cord WM, but not GM, observed in HD mice. Inactivation of mHTT in oligodendroglia had no effect on the density of oligodendroglial cells but enhanced the expression of myelin-related proteins in the spinal cord. Conclusion: Our findings demonstrate that the myelination abnormalities observed in brain WM structures in HD extend to the spinal cord and suggest that specific expression of mHTT in oligodendrocytes contributes to such abnormalities.

scholarly journals RNA Sequencing of Human Peripheral Blood Cells Indicates Upregulation of Immune-Related Genes in Huntington's Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Miguel A. Andrade-Navarro ◽  
Katja Mühlenberg ◽  
Eike J. Spruth ◽  
Nancy Mah ◽  
Adrián González-López ◽  
...  
Keyword(s):  
Gene Expression ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Gene Expression Signature ◽  
Interferon Response ◽  
Peripheral Blood Cells

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a trinucleotide repeat expansion in the Huntingtin gene. As disease-modifying therapies for HD are being developed, peripheral blood cells may be used to indicate disease progression and to monitor treatment response. In order to investigate whether gene expression changes can be found in the blood of individuals with HD that distinguish them from healthy controls, we performed transcriptome analysis by next-generation sequencing (RNA-seq). We detected a gene expression signature consistent with dysregulation of immune-related functions and inflammatory response in peripheral blood from HD cases vs. controls, including induction of the interferon response genes, IFITM3, IFI6 and IRF7. Our results suggest that it is possible to detect gene expression changes in blood samples from individuals with HD, which may reflect the immune pathology associated with the disease.

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