scholarly journals Genetic deletion of S6k1 does not rescue the phenotypic deficits observed in the R6/2 mouse model of Huntington’s disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Elaine E. Irvine ◽  
Loukia Katsouri ◽  
Florian Plattner ◽  
Hind Al-Qassab ◽  
Rand Al-Nackkash ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Mammalian Target Of Rapamycin ◽  
Protein Aggregate ◽  
Beneficial Effects ◽  
Age Related ◽  
Signalling Molecule ◽  
Mutant Huntingtin Protein

Abstract Huntington’s disease (HD) is a fatal inherited autosomal dominant neurodegenerative disorder caused by an expansion in the number of CAG trinucleotide repeats in the huntingtin gene. The disease is characterized by motor, behavioural and cognitive symptoms for which at present there are no disease altering treatments. It has been shown that manipulating the mTOR (mammalian target of rapamycin) pathway using rapamycin or its analogue CCI-779 can improve the cellular and behavioural phenotypes of HD models. Ribosomal protein S6 kinase 1 (S6K1) is a major downstream signalling molecule of mTOR, and its activity is reduced by rapamycin suggesting that deregulation of S6K1 activity may be beneficial in HD. Furthermore, S6k1 knockout mice have increased lifespan and improvement in age-related phenotypes. To evalute the potential benefit of S6k1 loss on HD-related phenotypes, we crossed the R6/2 HD model with the long-lived S6k1 knockout mouse line. We found that S6k1 knockout does not ameliorate behavioural or physiological phenotypes in the R6/2 mouse model. Additionally, no improvements were seen in brain mass reduction or mutant huntingtin protein aggregate levels. Therefore, these results suggest that while a reduction in S6K1 signalling has beneficial effects on ageing it is unlikely to be a therapeutic strategy for HD patients.

scholarly journals Huntington's Disease: An Immune Perspective

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Annapurna Nayak ◽  
Rafia Ansar ◽  
Sunil K. Verma ◽  
Domenico Marco Bonifati ◽  
Uday Kishore
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Typical Feature ◽  
Trinucleotide Repeats ◽  
Mutant Huntingtin Protein ◽  
Unexplored Area ◽  
Cag Trinucleotide Repeats ◽  
The Brain ◽  
Abnormal Expansion

Huntington's disease (HD) is a progressive neurodegenerative disorder that is caused by abnormal expansion of CAG trinucleotide repeats. Neuroinflammation is a typical feature of most neurodegenerative diseases that leads to an array of pathological changes within the affected areas in the brain. The neurodegeneration in HD is also caused by aberrant immune response in the presence of aggregated mutant huntingtin protein. The effects of immune activation in HD nervous system are a relatively unexplored area of research. This paper summarises immunological features associated with development and progression of HD.

scholarly journals The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Alba Di Pardo ◽  
Elena Ciaglia ◽  
Monica Cattaneo ◽  
Anna Maciag ◽  
Francesco Montella ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Motor Dysfunction ◽  
Cag Repeats ◽  
Huntingtin Protein ◽  
Human Microglia

Abstract The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) has been found significantly enriched in long-living individuals. Neuroinflammation is a key player in Huntington’s disease (HD), a neurodegenerative disorder caused by neural death due to expanded CAG repeats encoding a long polyglutamine tract in the huntingtin protein (Htt). Herein, we showed that striatal-derived cell lines with expanded Htt (STHdh Q111/111) expressed and secreted lower levels of BPIFB4, when compared with Htt expressing cells (STHdh Q7/7), which correlated with a defective stress response to proteasome inhibition. Overexpression of LAV-BPIFB4 in STHdh Q111/111 cells was able to rescue both the BPIFB4 secretory profile and the proliferative/survival response. According to a well-established immunomodulatory role of LAV-BPIFB4, conditioned media from LAV-BPIFB4-overexpressing STHdh Q111/111 cells were able to educate Immortalized Human Microglia—SV40 microglial cells. While STHdh Q111/111 dying cells were ineffective to induce a CD163 + IL-10high pro-resolving microglia compared to normal STHdh Q7/7, LAV-BPIFB4 transduction promptly restored the central immune control through a mechanism involving the stromal cell-derived factor-1. In line with the in vitro results, adeno-associated viral-mediated administration of LAV-BPIFB4 exerted a CXCR4-dependent neuroprotective action in vivo in the R6/2 HD mouse model by preventing important hallmarks of the disease including motor dysfunction, body weight loss, and mutant huntingtin protein aggregation. In this view, LAV-BPIFB4, due to its pleiotropic ability in both immune compartment and cellular homeostasis, may represent a candidate for developing new treatment for HD.

scholarly journals Bim contributes to the progression of Huntington’s disease-associated phenotypes

2019 ◽  
Vol 29 (2) ◽  
pp. 216-227
Author(s):  
Sheridan L Roberts ◽  
Tracey Evans ◽  
Yi Yang ◽  
Yuhua Fu ◽  
Robert W Button ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Death ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Brain Regions ◽  
Post Mortem ◽  
Polyglutamine Tract

Abstract Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin (HTT) protein. Mutant HTT (mHTT) toxicity is caused by its aggregation/oligomerization. The striatum is the most vulnerable region, although all brain regions undergo neuronal degeneration in the disease. Here we show that the levels of Bim, a BH3-only protein, are significantly increased in HD human post-mortem and HD mouse striata, correlating with neuronal death. Bim reduction ameliorates mHTT neurotoxicity in HD cells. In the HD mouse model, heterozygous Bim knockout significantly mitigates mHTT accumulation and neuronal death, ameliorating disease-associated phenotypes and lifespan. Therefore, Bim could contribute to the progression of HD.

scholarly journals Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease

2011 ◽  
Vol 21 (5) ◽  
pp. 1124-1137 ◽  
Author(s):  
Ashu Johri ◽  
Noel Y. Calingasan ◽  
Thomas M. Hennessey ◽  
Abhijeet Sharma ◽  
Lichuan Yang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transgenic Mouse ◽  
Mitochondrial Biogenesis ◽  
Transgenic Mouse Model ◽  
Beneficial Effects

scholarly journals Age-related axonal swellings precede other neuropathological hallmarks in a knock-in mouse model of Huntington's disease

2014 ◽  
Vol 35 (10) ◽  
pp. 2382-2393 ◽  
Author(s):  
Martina Marangoni ◽  
Robert Adalbert ◽  
Lucie Janeckova ◽  
Jane Patrick ◽  
Jaskaren Kohli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Related ◽  
Axonal Swellings

Beneficial effects of rolipram in the R6/2 mouse model of Huntington's disease

2008 ◽  
Vol 30 (3) ◽  
pp. 375-387 ◽  
Author(s):  
Zena DeMarch ◽  
Carmela Giampà ◽  
Stefano Patassini ◽  
Giorgio Bernardi ◽  
Francesca Romana Fusco
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Beneficial Effects

scholarly journals Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington’s disease

2019 ◽  
Vol 116 (49) ◽  
pp. 24840-24851 ◽  
Author(s):  
Ferah Yildirim ◽  
Christopher W. Ng ◽  
Vincent Kappes ◽  
Tobias Ehrenberger ◽  
Siobhan K. Rigby ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Beneficial Effects ◽  
Transcriptional Dysregulation ◽  
Clinical Onset ◽  
Transcriptional Changes ◽  
Chromatin Profiling

Huntington’s disease (HD) is a chronic neurodegenerative disorder characterized by a late clinical onset despite ubiquitous expression of the mutant Huntingtin gene (HTT) from birth. Transcriptional dysregulation is a pivotal feature of HD. Yet, the genes that are altered in the prodromal period and their regulators, which present opportunities for therapeutic intervention, remain to be elucidated. Using transcriptional and chromatin profiling, we found aberrant transcription and changes in histone H3K27acetylation in the striatum of R6/1 mice during the presymptomatic disease stages. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD.

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