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 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.

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 Localization and Regulation of the N Terminal Splice Variant of PGC-1αin Adult Skeletal Muscle Fibers

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Tiansheng Shen ◽  
Yewei Liu ◽  
Martin F. Schneider
Keyword(s):  
Skeletal Muscle ◽  
Splice Variant ◽  
Nuclear Export ◽  
Fiber Type ◽  
Muscle Fibers ◽  
Nuclear Accumulation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adult Skeletal Muscle ◽  
Skeletal Muscle Fibers

The transcriptional coactivator peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α) regulates expression of genes for metabolism and muscle fiber type. Recently, a novel splice variant of PGC-1α(NT-PGC-1α, amino acids 1–270) was cloned and found to be expressed in muscle. Here we use Flag-tagged NT-PGC-1αto examine the subcellular localization and regulation of NT-PGC-1αin skeletal muscle fibers. Flag-NT-PGC-1αis located predominantly in the myoplasm. Nuclear NT-PGC-1αcan be increased by activation of protein kinase A. Activation of p38 MAPK by muscle activity or of AMPK had no effect on the subcellular distribution of NT-PGC-1α. Inhibition of CRM1-mediated export only caused relatively slow nuclear accumulation of NT-PGC-1α, indicating that nuclear export of NT-PGC-1αmay be mediated by both CRM1-dependent and -independent pathways. Together these results suggest that the regulation of NT-PGC-1αin muscle fibers may be very different from that of the full-length PGC-1α, which is exclusively nuclear.

scholarly journals Peroxisome Proliferator-Activated Receptor-γin Amyotrophic Lateral Sclerosis and Huntington’s Disease

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
Mahmoud Kiaei
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
G93a Sod1 ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a debilitating and one of the most common adult-onset neurodegenerative diseases with the prevalence of about 5 per 100 000 individuals. It results in the progressive loss of upper and lower motor neurons and leads to gradual muscle weakening ultimately causing paralysis and death. ALS has an obscure cause and currently no effective treatment exists. In this review, a potentially important pathway is described that can be activated by peroxisome proliferator-activated receptor-γ(PPAR-γ) agonists and has the ability to block the neuropathological damage caused by inflammation in ALS and possibly in other neudegenerative diseases like Huntington's disease (HD). Neuroinflammation is a common pathological feature in neurodegenerative diseases. Therefore, PPAR-γagonists are thought to be neuroprotective in ALS and HD. We and others have tested the neuroprotective effect of pioglitazone (Actos), a PPAR-γagonist, in G93A SOD1 transgenic mouse model of ALS and found significant increase in survival of G93A SOD1 mice. These findings suggest that PPAR-γmay be an important regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. The involvement of PPAR-γin HD is currently under investigation, one study finds that the treatment with rosiglitazone had no protection in R6/2 transgenic mouse model of HD. PPAR-γcoactivator-1α(PGC-1α) is a transcriptional coactivator that works together with combination of other transcription factors like PPAR-γin the regulation of mitochondrial biogenesis. Therefore, PPAR-γis a possible target for ALS and HD as it functions as transcription factor that interacts with PGC-1α. In this review, the role of PPAR-γin ALS and HD is discussed based on the current literature and hypotheses.

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