Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington's disease

2015 ◽  
Vol 74 ◽  
pp. 25-31 ◽  
Author(s):  
Yasuo Miki ◽  
Kunikazu Tanji ◽  
Fumiaki Mori ◽  
Koichi Wakabayashi
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Intranuclear Inclusions ◽  
Cellular Model ◽  
Sigma 1 Receptor ◽  
Sigma 1

The sigma 1 receptor (S1R) is a potential therapeutic target for the treatment of Huntington's disease

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Endoplasmic Reticulum ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Therapeutic Target ◽  
Structural Integrity ◽  
Neuronal Cell ◽  
Glutamate Excitotoxicity ◽  
Potential Therapeutic Target ◽  
Sigma 1 Receptor ◽  
Sigma 1

During the progression of Huntington's disease (HD), changes in Ca2+ signaling cause neuronal cells to lose a range of functional properties. GABAergic medium spiny neurons (MSNs) are able to prevent Ca2+ imbalance in the early stages of the illness through a number of compensatory strategies. However, as people become older, their neuroprotective potential diminishes due to a decrease in metabolic activity and the generation of Ca2+-buffering proteins. Continuing Ca2+ regulation problems exhaust the cells' compensatory abilities, resulting in a continuous surge in cytosolic Ca2+ and neuronal degeneration.The sigma 1 receptor (S1R) is a potential therapeutic target for the treatment of HD because it regulates a number of cytosolic Ca2+-dependent signaling cascades. S1R activation by selective agonists protects neurons from glutamate excitotoxicity, reduces store-operated Ca2+ entry (SOCE) hyperactivation, and maintains the structural integrity of mitochondria-associated endoplasmic reticulum membranes (MAMs), which is required for synchronizing mitochondrial and endoplasmic reticulum (ER) activity to maintain cell bioenergetics balance. Because of the stability of Ca2+ signaling in neurons, pridopidine, a highly selective S1R agonist, has been demonstrated to protect neurons in cellular and animal models of HD.The synaptoprotective effect of pridopidine is very important since it is found in both cortical and striatal neurons, indicating that pridopidine has a systemic influence on HD therapy. Because synaptic dysfunctions are one of the earliest markers of neuropathology at the cellular level, normalization of Ca2+ balance by pridopidine may prevent disease development at the molecular level at the earliest stages. In this regard, the most significant therapeutic advantage of pridopidine will almost certainly be in preventative treatment, even before the start of the first clinical indications, which will improve neuronal cell compensatory abilities and significantly reduce the progression of HD.

Pridopidine in the treatment of Huntington’s disease

2020 ◽  
Vol 31 (4) ◽  
pp. 441-451 ◽  
Author(s):  
Magdalena Jabłońska ◽  
Klaudyna Grzelakowska ◽  
Bartłomiej Wiśniewski ◽  
Ewelina Mazur ◽  
Kamil Leis ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuroprotective Effect ◽  
Treatment Options ◽  
D2 Receptor ◽  
Cognitive Disorders ◽  
Symptomatic Treatment ◽  
Sigma 1 Receptor ◽  
Conduction Disorders ◽  
Sigma 1

AbstractHuntington’s disease (HD) is a highly common inherited monogenic neurodegenerative disease, and the gene responsible for its development is located in the 4p16.3 chromosome. The product of that gene mutation is an abnormal huntingtin (Htt) protein that disrupts the neural conduction, thus leading to motor and cognitive disorders. The disease progresses to irreversible changes in the central nervous system (CNS). Although only a few drugs are available to symptomatic treatment, ‘dopamine stabilizers’ (as represented by the pridopidine) may be the new treatment options. The underlying causes of HD are dopaminergic conduction disorders. Initially, the disease is hyperkinetic (chorea) until it eventually reaches the hypokinetic phase. Studies confirmed a correlation between the amount of dopamine in the CNS and the stage of the disease. Pridopidine has the capacity to be a dopamine buffer, which could increase or decrease the dopamine content depending on the disease phase. A research carried out on animal models demonstrated the protective effect of pridopidine on nerve cells thanks to its ability to alter the cortical glutamatergic signaling through the N-methyl-D-aspartate (NMDA) receptors. Studies on dopamine stabilizers also reported that pridopidine has a 100-fold greater affinity for the sigma-1 receptor than for the D2 receptor. Disturbances in the activity of sigma-1 receptors occur in neurodegenerative diseases, including HD. Their interaction with pridopidine results in the neuroprotective effect, which is manifested as an increase in the plasticity of synaptic neurons and prevention of their atrophy within the striatum. To determine the effectiveness of pridopidine in the treatment of HD, large multicenter randomized studies such as HART, MermaiHD, and PRIDE-HD were carried out.

Full length huntingtin is not detected in intranuclear inclusions in Huntington's disease brain

1998 ◽  
Vol 26 (3) ◽  
pp. S243-S243 ◽  
Author(s):  
Philip Thomas ◽  
Fiona Wilkinson ◽  
Nguyen thi Man ◽  
Peter S Harper ◽  
James W Neal ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Full Length ◽  
Intranuclear Inclusions

scholarly journals A Patient-Derived Cellular Model for Huntington’s Disease Reveals Phenotypes at Clinically Relevant CAG Lengths

2018 ◽  
Author(s):  
Claudia Lin-Kar Hung ◽  
Tamara Maiuri ◽  
Laura Erin Bowie ◽  
Ryan Gotesman ◽  
Susie Son ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Lines ◽  
Disease Onset ◽  
Cag Repeat ◽  
Dna Repeats ◽  
Cellular Model ◽  
Human Telomerase Reverse Transcriptase ◽  
Huntingtin Protein ◽  
Transformed Cell Lines

ABSTRACTThe huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington’s disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age-onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant ADP/ATP ratios and hypophosphorylated huntingtin protein. We additionally observed dysregulated ROS-dependent huntingtin localization to nuclear speckles in HD cells. We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single cell level, which, unlike transformed cell lines, maintains TP53 function critical for huntingtin transcriptional regulation and genomic integrity.

C01 The effect of mismatch repair proteins in a huntington’s disease cellular model

2021 ◽  
Author(s):  
Joseph Stone ◽  
Jasmine Donaldson ◽  
Sophie Powell ◽  
Nicholas Allen ◽  
Thomas Massey ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mismatch Repair ◽  
Cellular Model ◽  
Mismatch Repair Proteins

Characterization of adenine nucleotide metabolism in the cellular model of Huntington’s disease

2018 ◽  
Vol 37 (11) ◽  
pp. 630-638 ◽  
Author(s):  
Marta Toczek ◽  
Karolina Pierzynowska ◽  
Barbara- Kutryb-Zajac ◽  
Lidia Gaffke ◽  
Ewa M. Slominska ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Adenine Nucleotide ◽  
Nucleotide Metabolism ◽  
Cellular Model ◽  
Adenine Nucleotide Metabolism
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