scholarly journals Impaired Brain Energy Metabolism in the BACHD Mouse Model of Huntington's Disease: Critical Role of Astrocyte–Neuron Interactions

2014 ◽  
Vol 34 (9) ◽  
pp. 1500-1510 ◽  
Author(s):  
Lydie Boussicault ◽  
Anne-Sophie Hérard ◽  
Noel Calingasan ◽  
Fanny Petit ◽  
Carole Malgorn ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Cag Repeat ◽  
Metabolic Alterations ◽  
Culture Models ◽  
Repeat Expansions

Huntington's disease (HD) is caused by cytosine-adenine-guanine (CAG) repeat expansions in the huntingtin (Htt) gene. Although early energy metabolic alterations in HD are likely to contribute to later neurodegenerative processes, the cellular and molecular mechanisms responsible for these metabolic alterations are not well characterized. Using the BACHD mice that express the full-length mutant huntingtin (mHtt) protein with 97 glutamine repeats, we first demonstrated localized in vivo changes in brain glucose use reminiscent of what is observed in premanifest HD carriers. Using biochemical, molecular, and functional analyses on different primary cell culture models from BACHD mice, we observed that mHtt does not directly affect metabolic activity in a cell autonomous manner. However, coculture of neurons with astrocytes from wild-type or BACHD mice identified mutant astrocytes as a source of adverse non-cell autonomous effects on neuron energy metabolism possibly by increasing oxidative stress. These results suggest that astrocyte-to-neuron signaling is involved in early energy metabolic alterations in HD.

Deficits in Striatal Dopamine D2 Receptors and Energy Metabolism Detected by in Vivo MicroPET Imaging in a Rat Model of Huntington's Disease

2000 ◽  
Vol 166 (2) ◽  
pp. 287-297 ◽  
Author(s):  
Dalia M. Araujo ◽  
Simon R. Cherry ◽  
Keith J. Tatsukawa ◽  
Tatsushi Toyokuni ◽  
Harley I. Kornblum
Keyword(s):  
Energy Metabolism ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rat Model ◽  
D2 Receptors ◽  
Dopamine D2 Receptors ◽  
Striatal Dopamine ◽  
Micropet Imaging ◽  
Dopamine D2

scholarly journals New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Robert S. Lahue
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Model Systems ◽  
Triplet Repeat ◽  
Maximal Effect ◽  
Huntingtin Protein ◽  
Dna Repair Proteins ◽  
Repeat Expansions

Abstract Huntington’s disease (HD) is a fatal, inherited neurodegenerative disease that causes neuronal death, particularly in medium spiny neurons. HD leads to serious and progressive motor, cognitive and psychiatric symptoms. Its genetic basis is an expansion of the CAG triplet repeat in the HTT gene, leading to extra glutamines in the huntingtin protein. HD is one of nine genetic diseases in this polyglutamine (polyQ) category, that also includes a number of inherited spinocerebellar ataxias (SCAs). Traditionally it has been assumed that HD age of onset and disease progression were solely the outcome of age-dependent exposure of neurons to toxic effects of the inherited mutant huntingtin protein. However, recent genome-wide association studies (GWAS) have revealed significant effects of genetic variants outside of HTT. Surprisingly, these variants turn out to be mostly in genes encoding DNA repair factors, suggesting that at least some disease modulation occurs at the level of the HTT DNA itself. These DNA repair proteins are known from model systems to promote ongoing somatic CAG repeat expansions in tissues affected by HD. Thus, for triplet repeats, some DNA repair proteins seem to abandon their normal genoprotective roles and, instead, drive expansions and accelerate disease. One attractive hypothesis—still to be proven rigorously—is that somatic HTT expansions augment the disease burden of the inherited allele. If so, therapeutic approaches that lower levels of huntingtin protein may need blending with additional therapies that reduce levels of somatic CAG repeat expansions to achieve maximal effect.

scholarly journals Molecular mediators, environmental modulators and experience-dependent synaptic dysfunction in Huntington's disease.

2004 ◽  
Vol 51 (2) ◽  
pp. 415-430 ◽  
Author(s):  
Anthony J Hannan
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Environmental Enrichment ◽  
Molecular Mechanisms ◽  
Psychiatric Symptoms ◽  
Brain Regions ◽  
Cag Repeat ◽  
Autosomal Dominant Disorder ◽  
Gene Environment

Huntington's disease (HD) is an autosomal dominant disorder in which there is progressive neurodegeneration producing motor, cognitive and psychiatric symptoms. HD is caused by a trinucleotide (CAG) repeat mutation, encoding an expanded polyglutamine tract in the huntingtin protein. At least eight other neurodegenerative diseases are caused by CAG/glutamine repeat expansions in different genes. Recent evidence suggests that environmental factors can modify the onset and progression of Huntington's disease and possibly other neurodegenerative disorders. This review outlines possible molecular and cellular mechanisms mediating the polyglutamine-induced toxic 'gain of function' and associated gene-environment interactions in HD. Key aspects of pathogenesis shared with other neurodegenerative diseases may include abnormal protein-protein interactions, selective disruption of gene expression and 'pathological plasticity' of synapses in specific brain regions. Recent discoveries regarding molecular mechanisms of pathogenesis are guiding the development of new therapeutic approaches. Knowledge of gene-environment interactions, for example, could lead to development of 'enviromimetics' which mimic the beneficial effects of specific environmental stimuli. The effects of environmental enrichment on brain and behaviour will also be discussed, together with the general implications for neuroscience research involving animal models.

Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease

2010 ◽  
Vol 90 (3) ◽  
pp. 905-981 ◽  
Author(s):  
Chiara Zuccato ◽  
Marta Valenza ◽  
Elena Cattaneo
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Disease Process ◽  
Primary Source ◽  
Cag Repeat ◽  
Mutant Protein ◽  
Loss Of Function ◽  
Causative Gene

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.

scholarly journals Lack of RAN-mediated toxicity in Huntington’s disease knock-in mice

2020 ◽  
Vol 117 (8) ◽  
pp. 4411-4417 ◽  
Author(s):  
Su Yang ◽  
Huiming Yang ◽  
Luoxiu Huang ◽  
Luxiao Chen ◽  
Zhaohui Qin ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genome Editing ◽  
Mouse Models ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Behavioral Phenotypes ◽  
Endogenous Level ◽  
Ran Translation

Identification of repeat-associated non-AUG (RAN) translation in trinucleotide (CAG) repeat diseases has led to the emerging concept that CAG repeat diseases are caused by nonpolyglutamine products. Nonetheless, the in vivo contribution of RAN translation to the pathogenesis of CAG repeat diseases remains elusive. Via CRISPR/Cas9-mediated genome editing, we established knock-in mouse models that harbor expanded CAG repeats in the mouse huntingtin gene to express RAN-translated products with or without polyglutamine peptides. We found that RAN translation is not detected in the knock-in mouse models when expanded CAG repeats are expressed at the endogenous level. Consistently, the expanded CAG repeats that cannot be translated into polyglutamine repeats do not yield the neuropathological and behavioral phenotypes that were found in knock-in mice expressing expanded polyglutamine repeats. Our findings suggest that RAN-translated products do not play a major role in the pathogenesis of CAG repeat diseases and underscore the importance in targeting polyglutamine repeats for therapeutics.

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