Protein aggregation and neurodegeneration: Clues from a yeast model of Huntington’s disease

Бочарова, Наталья Александровна; Chave-Cox, R.; Sokolov, Svyatoslav S.; Knorre, Dmitry A.; Severin, Fedor F.

doi:10.1134/s0006297909020163

Cited by 13 publications

(10 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PolyQ expression (103Q but not 103QP) also induced ER stress leading to UPR (Duennwald and Lindquist, 2008), and has also been proposed to lead to lethal impairment of cell cycle progression (Bocharova et al, 2008, 2009). ER and cell cycle impairments are believed to be consequences of the impairment of specific branches of the UPS pathway by polyQ expression (103Q), including the ERAD and anaphase promoting complex (APC) pathways (Bocharova et al, 2008, 2009; Duennwald and Lindquist, 2008). The mitochondrion-associated protein degradation pathway (MAD) shares pivotal components with the ERAD pathway (Heo et al, 2010; Taylor and Rutter, 2011).…”

Section: Yeast Models Expressing Neurotoxic Proteinsmentioning

confidence: 99%

Ubiquitin-dependent proteolysis in yeast cells expressing neurotoxic proteins

Braun

2015

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Critically impaired protein degradation is discussed to contribute to neurodegenerative disorders, including Parkinson's, Huntington's, Alzheimer's, and motor neuron diseases. Misfolded, aggregated, or surplus proteins are efficiently degraded via distinct protein degradation pathways, including the ubiquitin-proteasome system, autophagy, and vesicular trafficking. These pathways are regulated by covalent modification of target proteins with the small protein ubiquitin and are evolutionary highly conserved from humans to yeast. The yeast Saccharomyces cerevisiae is an established model for deciphering mechanisms of protein degradation, and for the elucidation of pathways underlying programmed cell death. The expression of human neurotoxic proteins triggers cell death in yeast, with neurotoxic protein-specific differences. Therefore, yeast cell death models are suitable for analyzing the role of protein degradation pathways in modulating cell death upon expression of disease-causing proteins. This review summarizes which protein degradation pathways are affected in these yeast models, and how they are involved in the execution of cell death. I will discuss to which extent this mimics the situation in other neurotoxic models, and how this may contribute to a better understanding of human disorders.

show abstract

Section: Yeast Models Expressing Neurotoxic Proteinsmentioning

confidence: 99%

Ubiquitin-dependent proteolysis in yeast cells expressing neurotoxic proteins

Braun

2015

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…HD inheritance is autosomal dominant and consequently the prevailing view is that mHtt mediated symptoms result from a toxic gain-offunction mechanism although loss-of-function mechanisms for mHtt and Htt are also proposed [8,9]. Htt is conserved among vertebrates [10], is localized mainly in cytoplasm and exhibits anti-apopptotic properties [11,12]. Importantly, Htt expression in different tissues does not correspond with the restricted distribution of neuropathologic changes in HD [13] but the protein has been shown to be required for mammalian neurogenesis [14].…”

Section: Huntington's Diseasementioning

confidence: 99%

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

Karachitos¹,

Grobys²

2015

Pharmaceut Reg Affairs

View full text Add to dashboard Cite

It is becoming increasingly evident that mitochondria dysfunction plays an important role in pathogenesis of Huntington's disease (HD). However, the underlying mechanism is still needs to be explained. The crucial aspect of the explanation is to indicate the upstream events in mitochondria dysfunction that could contribute to HD. In the review we propose the defect of voltage-dependent anion-selective channel (VDAC), as a causative event in HDrelated mitochondria dysfunction. Thus, we propose to consider VDAC as a crucial element in HD etiology and consequently as a reasonable target for therapeutic interventions in HD, based on developing novel therapeutic strategies eliminating mitochondria dysfunction.Keywords: Huntington's disease; VDAC; Mitochondria; Therapy Huntington's DiseaseHuntington's disease (HD) is a progressive and fatal neurodegenerative disease with a prevalence of about 5-10/100 000. Clinically, the disease is characterized by progressive chorea (involuntary dance-like movements), rigidity, weight loss, dementia, seizures and psychiatric disturbances such as depression, withdrawal and irritability. These symptoms including cognitive deterioration, psychiatric disturbances, and movement disorders result from a selective and continuous loss of neurons from the striatum and deep layers of the cerebral cortex although other brain regions such as thalamus and subthalamic nucleus are also affected [1][2][3]. Current treatments for HD relieve merely the symptoms and address the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents [4,5] but are not able to restore neuronal function nor to stop the insidious loss of neurons. As summarized by Kumar et al. [6], although there is an intensive research concerning development of neuroprotective strategies such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (TGaseI), effective therapeutic strategies may not be developed until the next few decades. Thus, a new therapeutic approach involving new potential targets and to start before the symptomatic stage could contribute to HD treatment to be more specific and effective. This, in turn, requires further studies concerning molecular mechanisms underlying HD.The genetic hallmark of HD is an expansion of an unstable trinucleotide CAG repeat region within the first exon of the gene encoding the protein Huntington (Htt). This results in synthesis of its mutant form (mHtt) containing more than 36 glutamine residues at N terminus although the possible contribution of mHtt encoding mRNA, i.e. toxic mRNA in HD etiology has also been suggested [7]. HD inheritance is autosomal dominant and consequently the prevailing view is that mHtt mediated symptoms result from a toxic gain-offunction mechanism although loss-of-function mechanisms for mHtt and Htt are also proposed [8,9]. Htt is conserved among vertebrates [10], is localized mainly in cytoplasm and exhibits anti-apopptotic properties [11,12]. Importantly, Htt expression in diffe...

show abstract

“…In normal neurons, the late form of anaphase promoting complex (APC/C-Cdh1) constantly degrades PFKFB3, thereby suppressing the rate of glycolysis. [24,25] Alterations in the efficiency of different metabolic pathways can be due to damaged chaperonins that have been blocked by misfolded and aggregated protein forms. [23] A similar effect has also been observed upon artificial inhibition of this ubiquitinase, leading to a shift from respiration to glycolysis and the consequent oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] There is evidence that, in neurons affected by Alzheimer's, Parkinson's or Huntington's disease, the protein degradation machinery is overloaded by protein aggregates. [24,25] Alterations in the efficiency of different metabolic pathways can be due to damaged chaperonins that have been blocked by misfolded and aggregated protein forms. [26,27] Although the level of PFKFB3 has not been measured in affected neurons, it has recently been shown that APC/C-Cdh1 activity is inhibited during neuronal death induced by glutamate excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Structure‐Based Design of Small‐Molecule Ligands of Phosphofructokinase‐2 Activating or Inhibiting Glycolysis

et al. 2013

View full text Add to dashboard Cite

Glycolysis lies at the basis of metabolism and cell energy supply. The disregulation of glycolysis is involved in such pathological processes as cancer proliferation, neurodegenerative diseases, and amplification of ischemic damage. Phosphofructokinase-2 (PFK-2), a bifunctional enzyme and regulator of glycolytic flux, has recently emerged as a promising anticancer target. Herein, the computer-aided design of a new class of aminofurazan-triazole regulators of PFK-2 is described along with the results of their in vitro evaluation. The aminofurazan-triazoles differ from other recently described inhibitors of PFK-2 and demonstrate the ability to modulate glycolytic flux in rat muscle lysate, producing a twofold decrease by inhibitors and fourfold increase by activators. The most potent compounds in the series were shown to inhibit the kinase activity of the hypoxia-inducible form of PFK-2, PFKFB3, as well as proliferation of HeLa, lung adenocarcinoma, colon adenocarcinoma, and breast cancer cells at concentrations in the low micromolar range.

show abstract

Protein aggregation and neurodegeneration: Clues from a yeast model of Huntington’s disease

Cited by 13 publications

References 38 publications

Ubiquitin-dependent proteolysis in yeast cells expressing neurotoxic proteins

Ubiquitin-dependent proteolysis in yeast cells expressing neurotoxic proteins

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

Structure‐Based Design of Small‐Molecule Ligands of Phosphofructokinase‐2 Activating or Inhibiting Glycolysis

Contact Info

Product

Resources

About