Lowering Mutant Huntingtin Using Tricyclo-DNA Antisense Oligonucleotides As a Therapeutic Approach for Huntington's Disease

2019 ◽  
Vol 29 (5) ◽  
pp. 256-265 ◽  
Author(s):  
Marine Imbert ◽  
Florence Blandel ◽  
Christian Leumann ◽  
Luis Garcia ◽  
Aurelie Goyenvalle
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Antisense Oligonucleotides ◽  
Therapeutic Approach ◽  
Mutant Huntingtin

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 Embryonic Mutant Huntingtin Aggregate Formation in Mouse Models of Huntington’s Disease

2016 ◽  
Vol 5 (4) ◽  
pp. 343-346 ◽  
Author(s):  
Alexander P. Osmand ◽  
Terry Jo. Bichell ◽  
Aaron B. Bowman ◽  
Gillian P. Bates
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Mutant Huntingtin ◽  
Aggregate Formation

scholarly journals Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and Mutant Huntingtin Phenotypes in Huntington’s Disease Knock-In Mice

PLoS ONE ◽  
2012 ◽  
Vol 7 (9) ◽  
pp. e44273 ◽  
Author(s):  
Marina Kovalenko ◽  
Ella Dragileva ◽  
Jason St. Claire ◽  
Tammy Gillis ◽  
Jolene R. Guide ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin ◽  
Striatal Neurons

scholarly journals Mutant huntingtin induces iron overload via up-regulating IRP1 in Huntington’s disease

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Li Niu ◽  
Cuifang Ye ◽  
Yun Sun ◽  
Ting Peng ◽  
Shiming Yang ◽  
...  
Keyword(s):  
Iron Overload ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin

scholarly journals Caspase-6 does not contribute to the proteolysis of mutant huntingtin in the HdhQ150 knock-in mouse model of Huntington’s disease

PLoS Currents ◽  
2012 ◽  
Vol 4 ◽  
pp. e4fd085bfc9973 ◽  
Author(s):  
Christian Landles ◽  
Andreas Weiss ◽  
Sophie Franklin ◽  
David Howland ◽  
Gill Bates
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin ◽  
Caspase 6

scholarly journals N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation

2018 ◽  
Vol 115 (30) ◽  
pp. E7081-E7090 ◽  
Author(s):  
Laura E. Bowie ◽  
Tamara Maiuri ◽  
Melanie Alpaugh ◽  
Michelle Gabriel ◽  
Nicolas Arbez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Oxidative Dna Damage ◽  
Model Systems ◽  
Protective Effects ◽  
Mutant Huntingtin ◽  
Naturally Occurring ◽  
Phosphate Donor ◽  
High Content Analysis

The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA adducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.

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