Energy defects in Huntington's disease: Why “in vivo” evidence matters

Liot, Géraldine; Valette, Julien; Pépin, Jérémy; Flament, Julien; Brouillet, Emmanuel

doi:10.1016/j.bbrc.2016.09.065

Cited by 58 publications

(52 citation statements)

References 182 publications

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“…Nevertheless, in the presence of mHtt, iGAPDH can abnormally interact with the long polyglutamine of mHTT at the mitochondrial outer membrane, which blocks the iGAPDH signaling for degradation. Consequently, damaged mitochondria cannot be engulfed by lysosome and unfavorably accumulate in the mHtt-expressed cells, leading to cell death (Figure 1()) [78]. Both mitochondrial alterations and ROS can promote positive feedback loops, resulting in more OS and neuronal loss in the striatum and cortex [66].…”

Section: Huntington's Disease (Hd) and Reactive Oxygen Speciesmentioning

confidence: 99%

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications

Liu

Zhou

Ziegler

et al. 2017

Oxidative Medicine and Cellular Longevity

619

472

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Increasing numbers of individuals, particularly the elderly, suffer from neurodegenerative disorders. These diseases are normally characterized by progressive loss of neuron cells and compromised motor or cognitive function. Previous studies have proposed that the overproduction of reactive oxygen species (ROS) may have complex roles in promoting the disease development. Research has shown that neuron cells are particularly vulnerable to oxidative damage due to their high polyunsaturated fatty acid content in membranes, high oxygen consumption, and weak antioxidant defense. However, the exact molecular pathogenesis of neurodegeneration related to the disturbance of redox balance remains unclear. Novel antioxidants have shown great potential in mediating disease phenotypes and could be an area of interest for further research. In this review, we provide an updated discussion on the roles of ROS in the pathological mechanisms of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia, as well as a highlight on the antioxidant-based therapies for alleviating disease severity.

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Section: Huntington's Disease (Hd) and Reactive Oxygen Speciesmentioning

confidence: 99%

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications

Liu

Zhou

Ziegler

et al. 2017

Oxidative Medicine and Cellular Longevity

619

472

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“…In HD, for example, the toxic disease-causing protein is ubiquitously expressed, but initially, only the medium spiny neurons in the striatum (STR) are targeted for death (Arun et al, 2016; Carvalho et al, 2015; Reiner et al, 1988; Ross et al, 2017). Despite significant effort, however, researchers have yet to discover whether mitochondrial dysfunction is a cause of toxicity or a mechanism (reviewed in Brustovetsky, 2016; Liot et al, 2017; Polyzos and McMurray, 2017). …”

Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice

et al. 2019

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SUMMARY The basis for region-specific neuronal toxicity in Huntington disease is unknown. Here, we show that region-specific neuronal vulnerability is a substrate-driven response in astrocytes. Glucose is low in HdhQ(150/150) animals, and astrocytes in each brain region adapt by metabolically reprogramming their mitochondria to use endogenous, non-glycolytic metabolites as an alternative fuel. Each region is characterized by distinct metabolic pools, and astrocytes adapt accordingly. The vulnerable striatum is enriched in fatty acids, and mitochondria reprogram by oxidizing them as an energy source but at the cost of escalating reactive oxygen species (ROS)-induced damage. The cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentose phosphate shunt or gluconeogenesis pathways. ROS is not elevated, and this region sustains little damage. While mhtt expression imposes disease stress throughout the brain, sensitivity or resistance arises from an adaptive stress response, which is inherently region specific. Metabolic reprogramming may have relevance to other diseases.

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“…This feature allows for the dichotomization of HD patients into premanifest HD, i.e., gene carriers are clinically asymptomatic, and manifest HD, that is to say, after motor onset of the disease [77]. This mutation in the exon 1 of the gene encoding the Huntingtin protein (HTT) leads to a mutant HTT (mHTT) which is expressed by peripheral monocytes of premanifest HD patients [78], and induces both a loss of function (e.g., regulating intracellular transport, controlling apoptosis pathway) and a gain of toxic functions (e.g., abnormal protein-protein interaction, promoting pro-inflammatory cytokines) [79,80]. HD is neuropathologically characterized by the formation of intranuclear inclusions of mHTT [81] resulting in striatal, cortical and hypothalamic atrophy [82,83] which are associated with an accumulation of reactive microglia in these same regions [31,84].…”

Section: Clinical Input Of Tspo Pet Imaging In Neurodegenerative Dmentioning

confidence: 99%

Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases

Dupont

Largeau

Ribeiro

et al. 2017

IJMS

144

117

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In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease’s stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia’s role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis) was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases.

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Energy defects in Huntington's disease: Why “in vivo” evidence matters

Cited by 58 publications

References 182 publications

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications

Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice

Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases

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