Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?

Bono-Yagüe, José; Gómez-Escribano, Ana Pilar; Millán, José María; Vázquez‐Manrique, Rafael P.

doi:10.3390/antiox9070577

Cited by 35 publications

(23 citation statements)

References 263 publications

(320 reference statements)

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“…Despite the effort, it is not fully understood how polyQ-expanded proteins can be the cause of increased oxidative burden. Mutant proteins may interfere with numerous cellular processes which collectively lead to ROS production [ 66 ]. Toxic polyQ fragments associate with mitochondria and reduce their transport rate and their membrane potential [ 67 , 68 ].…”

Section: Oxidative Stress In Cellular and Animal Models Of Polyq Diseasesmentioning

confidence: 99%

Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases

et al. 2021

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Neurodegenerative polyglutamine (polyQ) disorders are caused by trinucleotide repeat expansions within the coding region of disease-causing genes. PolyQ-expanded proteins undergo conformational changes leading to the formation of protein inclusions which are associated with selective neuronal degeneration. Several lines of evidence indicate that these mutant proteins are associated with oxidative stress, proteasome impairment and microglia activation. These events may correlate with the induction of inflammation in the nervous system and disease progression. Here, we review the effect of polyQ-induced oxidative stress in cellular and animal models of polyQ diseases. Furthermore, we discuss the interplay between oxidative stress, neurodegeneration and neuroinflammation using as an example the well-known neuroinflammatory disease, Multiple Sclerosis. Finally, we review some of the pharmaceutical interventions which may delay the onset and progression of polyQ disorders by targeting disease-associated mechanisms.

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Section: Oxidative Stress In Cellular and Animal Models Of Polyq Diseasesmentioning

confidence: 99%

Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases

et al. 2021

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“…Approaches to improve the cellular environment, as can be achieved by hypoxic conditioning, are expected to represent a superior approach to target mitochondrial dysfunction in neurodegeneration [ 174 ] as compared to targeting specific downstream consequences of mitochondrial damage, in approaches targeting, for example, ROS or ATP levels in HD [ 215 , 216 ]. Hypoxic conditioning by itself is limited in many regards; age [ 217 ] and disease may blunt adaptive physiological and molecular adaptations and the selection of the hypoxic dose is a balancing act due to the danger inherent to severe hypoxia.…”

Section: Discussionmentioning

confidence: 99%

A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

Burtscher

Maglione

Pardo

et al. 2021

IJMS

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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.

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“…Recent combined microarray studies provide ample evidence for the induction of a protective oxidative response in HD-Q74 cells expressing mHTT [7]. Given the pathogenic impact of oxidative stress, strengthening of the endogenous antioxidant response represents a compelling therapeutic target for HD [23]. Based on this evidence, mHTT expression was induced in HD-Q74 cells with DOX for 3 days and ESC was added during the last 24 h of incubation with DOX to evaluate its protective effects against mHTT neurotoxicity.…”

Section: Neurotoxicity Induced By Mhtt In Hd-q74 Cellsmentioning

confidence: 99%

Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington’s Disease Models

et al. 2021

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Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene. This mutation leads to the production of mutant HTT (mHTT) protein which triggers neuronal death through several mechanisms. Here, we investigated the neuroprotective effects of esculetin (ESC), a bioactive phenolic compound, in an inducible PC12 model and a transgenic Drosophila melanogaster model of HD, both of which express mHTT fragments. ESC partially inhibited the progression of mHTT aggregation and reduced neuronal death through its ability to counteract the oxidative stress and mitochondria impairment elicited by mHTT in the PC12 model. The ability of ESC to counteract neuronal death was also confirmed in the transgenic Drosophila model. Although ESC did not modify the lifespan of the transgenic Drosophila, it still seemed to have a positive impact on the HD phenotype of this model. Based on our findings, ESC may be further studied as a potential neuroprotective agent in a rodent transgenic model of HD.

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Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?

Cited by 35 publications

References 263 publications

Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases

Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases

A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington’s Disease Models

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