Gene therapy by proteasome activator, PA28γ, improves motor coordination and proteasome function in Huntington’s disease YAC128 mice

Jeon, Jeha; Kim, Woori; Jang, Jiseon; Isacson, Ole; Seo, Hyemyung

doi:10.1016/j.neuroscience.2016.02.054

Cited by 38 publications

(32 citation statements)

References 39 publications

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“…Furthermore, genetic manipulation of BDNF in cortical neurons leads to morphological and behavioural deficits that are similar to symptomatic features of HD in mice, which highlights the protective role of BDNF on striatal neurons [80,88]. Measurement of BDNF in a mouse model of HD indicated an increase in both BDNF and proBDNF protein [89]. Also, evidence from transcriptional profiling studies demonstrates a close association of human HD with molecular and phenotypic correlates of BDNF depletion in the mouse cortex [88].…”

Section: Huntington’s Diseasementioning

confidence: 99%

Neurotrophin signalling: novel insights into mechanisms and pathophysiology

2016

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Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are prominent regulators of neuronal survival, growth and differentiation during development. While trophic factors are viewed as well-understood but not innovative molecules, there are many lines of evidence indicating that BDNF plays an important role in the pathophysiology of many neurodegenerative disorders, depression, anxiety and other psychiatric disorders. In particular, lower levels of BDNF are associated with the aetiology of Alzheimer’s and Huntington’s diseases. A major challenge is to explain how neurotrophins are able to induce plasticity, improve learning and memory and prevent age-dependent cognitive decline through receptor signalling. This article will review the mechanism of action of neurotrophins and how BDNF/tropomyosin receptor kinase B (TrkB) receptor signaling can dictate trophic responses and change brain plasticity through activity-dependent stimulation. Alternative approaches for modulating BDNF/TrkB signalling to deliver relevant clinical outcomes in neurodegenerative and neuropsychiatric disorders will also be described.

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Section: Huntington’s Diseasementioning

confidence: 99%

Neurotrophin signalling: novel insights into mechanisms and pathophysiology

2016

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“…Proteasome activity is generally inhibited in brain of HD patients. Jeon et al showed that transfer of the proteasome activator PA28γ gene into YAC128 HD mice enhances proteasome activity resulting in improved motor behavior (97).…”

Section: Correlation Between 26s Proteasome Dysfunction and Neurodegementioning

confidence: 99%

Precise assembly and regulation of 26S proteasome and correlation between proteasome dysfunction and neurodegenerative diseases

Im¹,

Chung²

2016

BMB Reports

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Neurodegenerative diseases (NDs) often involve the formation of abnormal and toxic protein aggregates, which are thought to be the primary factor in ND occurrence and progression. Aged neurons exhibit marked increases in aggregated protein levels, which can lead to increased cell death in specific brain regions. As no specific drugs/therapies for treating the symptoms or/and progression of NDs are available, obtaining a complete understanding of the mechanism underlying the formation of protein aggregates is needed for designing a novel and efficient removal strategy. Intracellular proteolysis generally involves either the lysosomal or ubiquitin-proteasome system. In this review, we focus on the structure and assembly of the proteasome, proteasome-mediated protein degradation, and the multiple dynamic regulatory mechanisms governing proteasome activity. We also discuss the plausibility of the correlation between changes in proteasome activity and the occurrence of NDs. [BMB Reports 2016; 49(9): 459-473]

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“…[83][84][85] mHtt causes the suppression of UPS function in the cells and brains of HD patients and in animal models, [86][87][88] while the enhancement of UPS activity enables soluble mHtt to degrade and improves proteasome function and motor coordination in HD. 63,[89][90][91][92][93][94] Macroautophagy, or autophagy, degrades aggregated proteins in the body by delivering them to the lysosome, and is essential for cellular function. 95 Htt has been found to function as an important regulator and substrate for selective autophagy.…”

Section: Excitotoxicity and Mitochondrial Dysfunctionsmentioning

confidence: 99%

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

Blum

Chern

Domenici

et al. 2018

Journal of Caffeine and Adenosine Research

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A 2A receptors (A 2A R), suggesting a possible involvement of adenosine and A 2A R is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A 2A R dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD.Keywords: Huntington's disease, adenosine, adenosine receptors, equilibrative nucleoside transporter, animal models Pathogenic Mechanisms of Huntington's DiseaseOverview H untington's disease (HD) is an inherited neurodegenerative disorder that is caused by a single, autosomal dominant gene mutation. HD generally affects young adults and is characterized by involuntary, abnormal movements and postures (chorea, dyskinesia, dystonia), psychiatric disturbances, and cognitive alterations.1,2 It is estimated that 1 in 10,000 people have HD and this disorder is fatal within 15-20 years after the onset of symptoms. Multiple brain regions, including several cortical and subcortical regions (cerebral cortex, layers III, V, and VI; pallidum, sub-thalamic nucleus, cerebellum), show signs of neurodegeneration, but the most pronounced neuronal loss is present in the caudate nucleus and the putamen of the striatum.3 Within the striatum, the striato-pallidal, medium spiny neurons (MSN) that express enkephalin, dopamine D 2 receptors (D 2 R) and adenosine A 2A receptors (A 2A R), 4,5 appear to be the most vulnerable.6,7

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Gene therapy by proteasome activator, PA28γ, improves motor coordination and proteasome function in Huntington’s disease YAC128 mice

Cited by 38 publications

References 39 publications

Neurotrophin signalling: novel insights into mechanisms and pathophysiology

Neurotrophin signalling: novel insights into mechanisms and pathophysiology

Precise assembly and regulation of 26S proteasome and correlation between proteasome dysfunction and neurodegenerative diseases

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

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