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 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 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 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 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 Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Eshan Khan ◽  
Subodh Kumar Mishra ◽  
Ribhav Mishra ◽  
Amit Mishra ◽  
Amit Kumar
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Small Molecules ◽  
Huntington’S Disease ◽  
Cag Repeats ◽  
Spinocerebellar Ataxias ◽  
Cellular Delivery ◽  
Lead Compounds ◽  
The Common ◽  
Search Approach

AbstractCAG repeats RNA causes various fatal neurodegenerative diseases exemplified by Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). Although there are differences in the pathogenic mechanisms, these diseases share the common cause, i.e., expansion of CAG repeats. The shared cause of these diseases raises the possibility for the exploiting the common target as a potential therapeutic approach. Oligonucleotide-based therapeutics are designed earlier with the help of the base pairing rule but are not very promiscuous, considering the nonspecific stimulation of the immune system and the poor cellular delivery. Therefore, small molecules-based therapeutics are preferred for targeting the repeats expansion disorders. Here, we have used the chemical similarity search approach to discern the small molecules that selectively target toxic CAG RNA. The lead compounds showed the specificity towards AA mismatch in biophysical studies including CD, ITC, and NMR spectroscopy and thus aided to forestall the polyQ mediated pathogenicity. Furthermore, the lead compounds also explicitly alleviate the polyQ mediated toxicity in HD cell models and patient-derived cells. These findings suggest that the lead compound could act as a chemical probe for AA mismatch containing RNA as well as plays a neuroprotective role in fatal neurodegenerative diseases like HD and SCAs.

Neurodegenerative diseases and Flavonoids: Special reference to kaempferol

2021 ◽  
Vol 20 ◽  
Author(s):  
Rahul ◽  
Yasir Hasan Siddique
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuroprotective Effects ◽  
Major Health Problem ◽  
Beneficial Effects

: Neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington’s disease, Multiple Sclerosis and Ischemic stroke have become a major health problem worldwide. Pre-clinical studies have demonstrated the beneficial effects of flavonoids on neurodegenerative diseases and suggesting them to be used as therapeutic agents. Kaempferol is found in many plants such as tea, beans, broccoli,strawberriesand has neuroprotective effects against the development of many neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's disease. The present study summarizesthe neuroprotective effects of kaempferol in various models of neurodegenerative diseases. Kaempferol delays the initiation as well as the progression of neurodegenerative disorders by acting as a scavenger of free radicals and preserving the activity of various antioxidant enzymes. Kaempferolcan crossthe blood-brain barrier (BBB), and therefore results inan enhanced protective effect. The multi-target property of kaempferol makes it a potential dietary supplement in preventing and treating neurodegenerative diseases.

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