scholarly journals A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

2021 ◽  
Vol 22 (2) ◽  
pp. 582
Author(s):  
Johannes Burtscher ◽  
Vittorio Maglione ◽  
Alba Di Pardo ◽  
Grégoire P. Millet ◽  
Christoph Schwarzer ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Drug Targets ◽  
Ion Homeostasis ◽  
Brain Regions ◽  
Molecular Pathways ◽  
Cellular Functions ◽  
Cellular Environment ◽  
Δ Opioid Receptor

Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington’s disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington’s disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington’s disease from this knowledge base.

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.

scholarly journals Molecular Strategies to Target Protein Aggregation in Huntington’s Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Olga D. Jarosińska ◽  
Stefan G. D. Rüdiger
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
The Novel ◽  
Cellular Functions ◽  
Knowledge Based ◽  
Current State ◽  
Ubiquitin Proteasome ◽  
Mrna Targeting

Huntington’s disease (HD) is a neurodegenerative disorder caused by the aggregation of the mutant huntingtin (mHTT) protein in nerve cells. mHTT self-aggregates to form soluble oligomers and insoluble fibrils, which interfere in a number of key cellular functions. This leads to cell quiescence and ultimately cell death. There are currently still no treatments available for HD, but approaches targeting the HTT levels offer systematic, mechanism-driven routes towards curing HD and other neurodegenerative diseases. This review summarizes the current state of knowledge of the mRNA targeting approaches such as antisense oligonucleotides and RNAi system; and the novel methods targeting mHTT and aggregates for degradation via the ubiquitin proteasome or the autophagy-lysosomal systems. These methods include the proteolysis-targeting chimera, Trim-Away, autophagosome-tethering compound, autophagy-targeting chimera, lysosome-targeting chimera and approach targeting mHTT for chaperone-mediated autophagy. These molecular strategies provide a knowledge-based approach to target HD and other neurodegenerative diseases at the origin.

scholarly journals Identification of potential proteins and microRNAs in Multiple Sclerosis and Huntington's diseases using in silico methods.

2021 ◽  
Author(s):  
Souvik Chakraborty ◽  
Tarasankar Maiti
Keyword(s):  
Multiple Sclerosis ◽  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
In Silico ◽  
Drug Targets ◽  
Gene Expression Omnibus ◽  
Hub Genes ◽  
Expression Of Genes ◽  
In Silico Methods

Neurogenerative diseases like multiple sclerosis, Huntington's disease are the major roadblocks in the way towards a healthy brain. Neurodegenerative diseases like multiple sclerosis and Huntington's disease are affected by several factors such as environmental, immunological, genetics, and the worse scenario we can think of is that they are on the rise worldwide. Degenerative diseases specifically target a limited group of neurons at first resulting in the loss of specific functions associated with the specific part of the brain. The early diagnosis of these neurodegenerative diseases is important so that treatments can start from the early stages of these diseases. In this study, we have established a link between Multiple sclerosis and Huntington's disease, and also we were able to establish the possible microRNAs that were connected to the expression of genes associated with these two diseases. In this present study, we analyzed the microarray datasets obtained from Gene Expression Omnibus and we identified 266 differentially expressed genes tried to identify using in silico methods the Hub genes involved in Multiple sclerosis and Huntington's disease. After identifying the genes and proteins we tried to identify the microRNAs that are interacting with the Hub genes. In our study, we identified that the protein network has PTPRC, CXCL8, RBM25 proteins that have maximum connectivity. The top Hub genes are then subjected to a database that contains information concerning the microRNAs that are interacting with the Hub proteins as well as with each other. According to our study, the hsa-mir-155-5p has one of the highest degrees in the microRNA network. Our study will be useful in the future for the development of new drug targets for these neurodegenerative diseases.

scholarly journals The regulatory roles of microRNAs toward pathogenesis and treatments in Huntington's disease

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Chih-Wei Tung ◽  
Pin-Yu Huang ◽  
Siew Chin Chan ◽  
Pei-Hsun Cheng ◽  
Shang-Hsun Yang
Keyword(s):  
Gene Regulation ◽  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Cognitive Ability ◽  
Huntington’S Disease ◽  
Genetic Diseases ◽  
Cellular Functions ◽  
Inherited Diseases ◽  
Mirna Targets ◽  
Non Coding Rna

AbstractHuntington’s disease (HD) is one of neurodegenerative diseases, and is defined as a monogenetic disease due to the mutation of Huntingtin gene. This disease affects several cellular functions in neurons, and further influences motor and cognitive ability, leading to the suffering of devastating symptoms in HD patients. MicroRNA (miRNA) is a non-coding RNA, and is responsible for gene regulation at post-transcriptional levels in cells. Since one miRNA targets to several downstream genes, it may regulate different pathways simultaneously. As a result, it raises a potential therapy for different diseases using miRNAs, especially for inherited diseases. In this review, we will not only introduce the update information of HD and miRNA, but also discuss the development of potential miRNA-based therapy in HD. With the understanding toward the progression of miRNA studies in HD, we anticipate it may provide an insight to treat this devastating disease, even applying to other genetic diseases.

scholarly journals Genesis of ER stress in Huntington’s Disease

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Marina Shenkman ◽  
Hagit Eiger ◽  
Gerardo Z. Lederkremer
Keyword(s):  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Late Onset ◽  
Genetic Disorder ◽  
Effective Therapy ◽  
Major Mechanism ◽  
Shed Light

AbstractRecent research has identified ER stress as a major mechanism implicated in cytotoxicity in many neurodegenerative diseases, among them Huntington’s disease. This genetic disorder is of late-onset, progressive and fatal, affecting cognition and movement. There is presently no cure nor any effective therapy for the disease. This review focuses on recent findings that shed light on the mechanisms of the advent and development of ER stress in Huntington’s disease and on its implications, highlighting possible therapeutic avenues that are being or could be explored.

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.

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