scholarly journals Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease

1999 ◽  
Vol 354 (1386) ◽  
pp. 981-989 ◽  
Author(s):  
Jang-Ho J. Cha ◽  
Ariel S. Frey ◽  
Stephen A. Alsdorf ◽  
Julie A. Kerner ◽  
Christoph M. Kosinski ◽  
...  

Alterations in neurotransmitter receptors are a pathological hallmark of the neurodegeneration seen in Huntington's disease (HD). However, the significance of these alterations has been uncertain, possibly reflecting simply the loss of brain cells. It is not known for certain whether the alteration of neurotransmitter receptors occurs before the onset of symptoms in human HD. Recently we developed transgenic mice that contain a portion of a human HD gene and develop a progressive abnormal neurological phenotype. Neurotransmitter receptors that are altered in HD (receptors for glutamate, dopamine, acetylcholine and adenosine) are decreased in the brain of transgenic mice, in some cases before the onset of behavioural or motor symptoms. In transgenic mice, neurotransmitter receptor alterations occur before neuronal death. Further, receptor alterations are selective in that certain receptors, namely N -methyl-D-aspartate and γ-aminobutyric acid receptors, are unaltered. Finally, receptor decreases are preceded by selective decreases in the corresponding mRNA species, suggesting the altered transcription of specific genes. These results suggest that (i) receptor decreases precede, and therefore might contribute to, the development of clinical symptoms, and (ii) altered transcription of specific genes might be a key pathological mechanism in HD.

2003 ◽  
Vol 85 (6) ◽  
pp. 1359-1367 ◽  
Author(s):  
Alpaslan Dedeoglu ◽  
James K. Kubilus ◽  
Lichuan Yang ◽  
Kimberly L. Ferrante ◽  
Steven M. Hersch ◽  
...  

2018 ◽  
Vol 5 (1) ◽  
Author(s):  
Lucía Gabriela García-Lara ◽  
Adriana Morales-Martínez ◽  
Quetzalli Denisse Angeles-López ◽  
Hilda Pedraza-Espitia ◽  
Iván Pérez-Neri ◽  
...  

Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the central nervous system that mainly affects the basal ganglia and has no cure. The mutation is located at an abnormal expansion of the CAG triplet in the Huntingtin gene. Humans show psychiatric, behavioural and motor disorders. Transgenic animal models are essential to the study of HD since the disease only affects humans. Therefore, the aim of this article was to describe the formation and maintenance of and to validate the progressive neurological phenotype of an R6/1 transgenic mouse colony. To achieve our objective, the colony founder was imported from Jackson Laboratories, and the mice were kept under controlled environmental conditions. The animals were bred at the vivarium of the Instituto Nacional de Neurología y Neurocirugía Man­uel Velasco Suárez. The R6/1 transgenic mice were successfully bred and showed genetic and phenotypic characteristics similar to the ones previously reported. Our colony is currently established and validated with the condi­tions of our vivarium and has produced more than four generations of R6/1 mice. The establishment of the R6/1 colony and its maintenance through generation is an advantage since it allows us to follow the authenticity of the transgenic mice regarding their phenotypic and motor behaviours. Fur­thermore, these animals can be compared with other transgenic mice that reproduce some of the main characteristics of the disease manifested in hu­mans, making these transgenic R6/1 mice a useful tool for the study of HD.


2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Annapurna Nayak ◽  
Rafia Ansar ◽  
Sunil K. Verma ◽  
Domenico Marco Bonifati ◽  
Uday Kishore

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.


2020 ◽  
Author(s):  
Giulia Birolini ◽  
Marta Valenza ◽  
Ilaria Ottonelli ◽  
Alice Passoni ◽  
Monica Favagrossa ◽  
...  

AbstractSupplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the bloodbrain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.


2021 ◽  
Vol 22 (22) ◽  
pp. 12499
Author(s):  
Chaebin Kim ◽  
Ali Yousefian-Jazi ◽  
Seung-Hye Choi ◽  
Inyoung Chang ◽  
Junghee Lee ◽  
...  

Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.


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