Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice

Human Molecular Genetics
Vanessa WheelerMarcy E MacDonald

Abstract

In Huntington's disease (HD), CAG repeats extend a glutamine tract in huntingtin to initiate the dominant loss of striatal neurons and chorea. Neuropathological changes include the formation of insoluble mutant N-terminal fragment, as nuclear/neuropil inclusions and filter-trap amyloid, which may either participate in the disease process or be a degradative by-product. In young Hdh knock-in mice, CAGs that expand the glutamine tract in mouse huntingtin to childhood-onset HD lengths lead to nuclear accumulation of full-length mutant huntingtin and later accumulation of insoluble fragment. Here we report late-onset neurodegeneration and gait deficits in older Hdh(Q111) knock-in mice, demonstrating that the nuclear phenotypes comprise early stages in a disease process that conforms to genetic and pathologic criteria determined in HD patients. Furthermore, using the early nuclear-accumulation phenotypes as surrogate markers, we show in genetic experiments that the disease process, initiated by full-length mutant protein, is hastened by co-expression of mutant fragment; therefore, accrual of insoluble-product in already compromised neurons may exacerbate pathogenesis. In contrast, timing of early disease events was not altered by no...Continue Reading

Associated Clinical Trials

Citations

Sep 8, 2012·Molecular Neurobiology·Maciej FigielWlodzimierz J Krzyzosiak
Mar 8, 2005·Neuroscience·S J Tallaksen-GreeneR L Albin
Mar 27, 2003·Progress in Neuro-psychopharmacology & Biological Psychiatry·Miriam A Hickey, Marie Françoise Chesselet
May 16, 2006·Nature Neuroscience·Anat YanaiMichael R Hayden
Apr 22, 2004·Nature Reviews. Neuroscience·M Flint Beal, Robert J Ferrante
Apr 25, 2012·Proceedings of the National Academy of Sciences of the United States of America·Zachary R Crook, David E Housman
May 13, 2009·The Journal of Biological Chemistry·Alisia CarnemollaFrancesca Persichetti
Jul 10, 2010·Human Molecular Genetics·Mary Y HengPeter J Detloff
May 4, 2011·Human Molecular Genetics·Jessie C JacobsenJong-Min Lee
Nov 28, 2013·Annual Review of Genetics·Stanley B Prusiner
Apr 10, 2007·Annual Review of Neuroscience·Harry T Orr, Huda Y Zoghbi
Jan 31, 2012·Neurology Research International·Tatyana VagnerAlexandre Mouravlev
Nov 2, 2011·Neuro-degenerative Diseases·J Robert ChangBassel E Sawaya
Apr 11, 2006·The Journal of Clinical Investigation·Maria Borrell-PagèsSandrine Humbert
Oct 12, 2011·The Journal of Clinical Investigation·Guy KeryerFrédéric Saudou
Jun 14, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Michelle GrayX William Yang
Feb 18, 2005·NeuroRx : the Journal of the American Society for Experimental NeuroTherapeutics·Steven M Hersch, Robert J Ferrante
Jan 4, 2006·NeuroRx : the Journal of the American Society for Experimental NeuroTherapeutics·Liliana B Menalled
Jul 31, 2013·Neuromolecular Medicine·Laura RuéEsther Pérez-Navarro
Apr 7, 2005·Proceedings of the National Academy of Sciences of the United States of America·Scott Q HarperBeverly L Davidson
Oct 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Alice GrisonGiannino Del Sal
Jan 27, 2015·Clinica Chimica Acta; International Journal of Clinical Chemistry·Yoshinao MuroMasashi Akiyama
Apr 18, 2012·Molecular and Cellular Neurosciences·James J RitchKimberly B Kegel
Oct 19, 2011·Brain Research Bulletin·Simon P BrooksStephen B Dunnett
Aug 23, 2011·Brain Research Bulletin·K R BowlesL Jones
Mar 2, 2011·Brain Research Reviews·R Lalonde, C Strazielle
May 12, 2010·Brain Research Bulletin·Simon BrooksStephen B Dunnett
Jul 19, 2012·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Ivan TkacJanet M Dubinsky
Jul 22, 2008·Neurobiology of Disease·Mary Y HengRoger L Albin
Dec 21, 2004·Alcoholism, Clinical and Experimental Research·Ajit KaleThomas G Hampton
Aug 5, 2009·Journal of Neurochemistry·Peter O Bauer, Nobuyuki Nukina

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.