Mitochondrial Dysfunction in Huntington’s disease: Pathogenesis and Therapeutic Opportunities

2021 ◽  
Vol 22 ◽  
Author(s):  
Aditi Sharma ◽  
Tapan Behl ◽  
Lalit Sharma ◽  
Lotfi Aelya ◽  
Simona Bungau
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Symptoms ◽  
Neuronal Degeneration ◽  
Cag Repeats ◽  
Ros Generation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Psychiatric Disturbances ◽  
Apoptotic Pathways

: Huntington’s disease (HD) is prototypical neurodegenerative disease, preferentially disrupts the neurons of striatum and cor-tex. Progressive motor dysfunctions, psychiatric disturbances, behavioural impairments and cognitive decline are the clinical symptoms of HD progression. The disease occurs due to, expanded CAG repeats in exon 1 of huntingtin protein (mHtt) causing its aggregation. Multiple cellular and molecular pathways are involved in the HD pathology. Mitochondria as vital organelles has an important role in most of the neurodegenerative diseases like HD. Over the years, the role of mitochondria in neurons are highly diverged, it not only contribute as cell power source, but as a dynamic organelles it fragments and then fuse to attain a maximal bioenergetics performance, regulate intracellular calcium homeostasis, reactive oxygen species (ROS) generation, antioxidant activity and involved in apoptotic pathways. Indeed, these events are seen to be affected in HD, resulting in neuronal dysfunction in pre-symptomatic stages. mHtt causes critical transcriptional abnormality by altering the expression of a master co-regulator, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), leading to increased susceptibility to oxidative stress and neuronal degeneration. Moreover, mHtt influences multiple cellular signal-ling events which ends with mitochondrial biogenesis. Here, we resume recent findings that pose mitochondria as an im-portant regulatory organelle in HD and how mHtt affects mitochondrial function, trafficking and homeostasis and makes neurons prone to degeneration. In addition, we also uncover the mitochondrial based potential targets and therapeutic ap-proaches with imminent or currently ongoing clinical trials.

scholarly journals Truncated Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α Splice Variant Is Severely Altered in Huntington’s Disease

2011 ◽  
Vol 8 (6) ◽  
pp. 496-503 ◽  
Author(s):  
Ashu Johri ◽  
Anatoly A. Starkov ◽  
Abhishek Chandra ◽  
Thomas Hennessey ◽  
Abhijeet Sharma ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Splice Variant ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals Genomic architecture differences at the HTT locus associated with symptomatic and pre-symptomatic cases of Huntington’s disease in a pilot study

2021 ◽  
pp. 1-6
Author(s):  
Matthew Salter ◽  
Ryan Powell ◽  
Jennifer Back ◽  
Francis Grand ◽  
Christina Koutsothanasi ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Symptoms ◽  
Disease Onset ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Healthy Controls ◽  
Chromosome Conformation ◽  
Chromatin Architecture ◽  
Patient Groups

Huntington’s Disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide Cytosine-Adenine-Guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this presymptomatic phase. Using peripheral blood samples from HD patients and healthy controls we used EpiSwitch®, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of the HTT gene. We evaluated chromatin conformations at 20 sites across 225 kb of the HTT locus in a small cohort of healthy controls, verified symptomatic HD patients (CAG, n>39) and patients with CAG expansions who had not yet manifested clinical symptoms of HD. Discrete chromosome conformations were observed across the patient groups. We found two constitutive interactions (occurring in all patient groups) and seven conditional interactions which were present in HD, but not in healthy controls. Most important, we observed three conditional interactions that were present only in HD patients manifesting clinical symptoms (symptomatic cases), but not in presymptomatic cases. 85% (6 out of 7) of the patients in the symptomatic HD cohort demonstrated at least one of the specific chromosome conformations associated with symptomatic HD. Our results provide the first evidence that chromatin architecture at the HTT locus is systemically altered in patients with HD, with conditional differences between clinical stages. Given the high clinical need in having a molecular tool to assess disease progression in HD, these results strongly suggest that the non-invasive assessment of Chromosome Conformation Signatures (CCS) warrant further study as a prognostic tool in HD.

scholarly journals Genomic architecture differences at the HTT locus underlie symptomatic and pre-symptomatic cases of Huntington’s disease.

F1000Research ◽  
2019 ◽  
Vol 7 ◽  
pp. 1757
Author(s):  
Matthew Salter ◽  
Ryan Powell ◽  
Jennifer Back ◽  
Francis Grand ◽  
Christina Koutsothanasi ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Symptoms ◽  
Disease Onset ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Healthy Controls ◽  
Chromosome Conformation ◽  
Chromatin Architecture ◽  
Patient Groups

Background:Huntington’s disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide cytosine-adenine-guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this pre-symptomatic phase.Methods:Using peripheral blood samples from HD patients and healthy controls we usedEpiSwitch™, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of theHTTgene. We evaluated chromatin conformations at 20 sites across 225 kb of theHTTlocus in healthy controls, verified symptomatic HD patients (CAG, n>39) and patients with CAG expansions who had not yet manifested clinical symptoms of HD.Results:Discrete chromosome conformations were observed across the patient groups. We found two constitutive interactions (occurring in all patient groups) and seven conditional interactions which were present in HD, but not in healthy controls. Most important, we observed three conditional interactions that were present only in HD patients manifesting clinical symptoms (symptomatic cases), but not in presymptomatic cases. Of the patients in the symptomatic HD cohort, 86% (6 out of 7) demonstrated at least one of the specific chromosome conformations associated with symptomatic HD.Conclusion:Our results provide the first evidence that chromatin architecture at theHTTlocus is systemically altered in patients with HD, with conditional differences between clinical stages. Given the high clinical need in having a molecular tool to assess disease progression in HD, these results strongly suggest that the non-invasive assessment of chromosome conformation signatures can be a valuable addition to prognostic assessment of HD patients.

scholarly journals Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor gamma

2010 ◽  
Vol 19 (20) ◽  
pp. 4043-4058 ◽  
Author(s):  
Ming-Chang Chiang ◽  
Chiung-Mei Chen ◽  
Maw-Rong Lee ◽  
Hsiao-Wen Chen ◽  
Hui-Mei Chen ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Energy Deficiency

Transcriptional dysregulation in Huntington’s Disease. The role in pathogenesis and potency for pharmacological targeting.

2020 ◽  
Vol 27 ◽  
Author(s):  
Aleksandra Pogoda ◽  
Natalia Chmielewska ◽  
Piotr Maciejak ◽  
Janusz Szyndler
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Regulatory Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Molecular Manipulation

: Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene that encodes a critical cell regulatory protein, huntingtin (Htt). The expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats causes improper folding of functional proteins and is an initial trigger of pathological changes in the brain. Recent research has indicated that the functional dysregulation of many transcription factors underlies the neurodegenerative processes that accompany HD. These disturbances are caused not only by the loss of wild-type Htt (WT Htt) function but also by the occurrence of abnormalities that result from the action of mutant Htt (mHtt). In this review, we aim to describe the role of transcription factors that are currently thought to be strongly associated with HD pathogenesis, namely, RE1-silencing transcription factor, also known as neuron-restrictive silencer factor (REST/NRSF), forkhead box proteins (FOXPs), peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1α), heat shock transcription factor 1 (HSF1), and nuclear factor κ light-chain-enhancer of activated B cells (NF-κB). We also take into account the role of these factors in the phenotype of HD as well as potential pharmacological interventions targeting the analyzed proteins. Furthermore, we considered whether molecular manipulation resulting in changes in transcription factor function may have clinical potency for treating HD.

scholarly journals Therapeutic Advances for Huntington’s Disease

2020 ◽  
Vol 10 (1) ◽  
pp. 43 ◽  
Author(s):  
Ashok Kumar ◽  
Vijay Kumar ◽  
Kritanjali Singh ◽  
Sukesh Kumar ◽  
You-Sam Kim ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Involuntary Movement ◽  
Cag Repeats ◽  
Transcriptional Dysregulation ◽  
Psychiatric Disturbances ◽  
Personality Changes ◽  
New Gene ◽  
Therapeutic Research ◽  
Analytical Tools

Huntington’s disease (HD) is a progressive neurological disease that is inherited in an autosomal fashion. The cause of disease pathology is an expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin gene (HTT) on chromosome 4 (4p16.3), which codes the huntingtin protein (mHTT). The common symptoms of HD include motor and cognitive impairment of psychiatric functions. Patients exhibit a representative phenotype of involuntary movement (chorea) of limbs, impaired cognition, and severe psychiatric disturbances (mood swings, depression, and personality changes). A variety of symptomatic treatments (which target glutamate and dopamine pathways, caspases, inhibition of aggregation, mitochondrial dysfunction, transcriptional dysregulation, and fetal neural transplants, etc.) are available and some are in the pipeline. Advancement in novel therapeutic approaches include targeting the mutant huntingtin (mHTT) protein and the HTT gene. New gene editing techniques will reduce the CAG repeats. More appropriate and readily tractable treatment goals, coupled with advances in analytical tools will help to assess the clinical outcomes of HD treatments. This will not only improve the quality of life and life span of HD patients, but it will also provide a beneficial role in other inherited and neurological disorders. In this review, we aim to discuss current therapeutic research approaches and their possible uses for HD.

scholarly journals Genomic architecture differences at the HTT locus associated with symptomatic and pre-symptomatic cases of Huntington’s disease in a pilot study.

F1000Research ◽  
2019 ◽  
Vol 7 ◽  
pp. 1757 ◽  
Author(s):  
Matthew Salter ◽  
Ryan Powell ◽  
Jennifer Back ◽  
Francis Grand ◽  
Christina Koutsothanasi ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Symptoms ◽  
Disease Onset ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Healthy Controls ◽  
Chromosome Conformation ◽  
Chromatin Architecture ◽  
Patient Groups

Background:Huntington’s disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide cytosine-adenine-guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this pre-symptomatic phase.Methods:Using peripheral blood samples from HD patients and healthy controls we usedEpiSwitch™, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of theHTTgene. We evaluated chromatin conformations at 20 sites across 225 kb of theHTTlocus in a small cohort of healthy controls, verified symptomatic HD patients (CAG, n>39) and patients with CAG expansions who had not yet manifested clinical symptoms of HD.Results:Discrete chromosome conformations were observed across the patient groups. We found two constitutive interactions (occurring in all patient groups) and seven conditional interactions which were present in HD, but not in healthy controls. Most important, we observed three conditional interactions that were present only in HD patients manifesting clinical symptoms (symptomatic cases), but not in presymptomatic cases. Of the patients in the symptomatic HD cohort, 86% (6 out of 7) demonstrated at least one of the specific chromosome conformations associated with symptomatic HD.Conclusion:Our results provide the first evidence that chromatin architecture at theHTTlocus is systemically altered in patients with HD, with conditional differences between clinical stages. Given the high clinical need in having a molecular tool to assess disease progression in HD, these results strongly suggest that the non-invasive assessment of chromosome conformation signatures warrant further study as a prognostic tool in HD.

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