PolyQ length-dependent metabolic alterations and DNA damage drive human astrocyte dysfunction in Huntington’s disease

Lange, Jenny; Gillham, Olivia; Flower, Michael; Ging, Heather; Eaton, Simon; Kapadia, Sneha; Neueder, Andreas; Duchen, Michael R.; Ferretti, Patrizia; Tabrizi, Sarah J

doi:10.1016/j.pneurobio.2023.102448

Cited by 9 publications

(9 citation statements)

References 90 publications

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“…Additionally, evidence that DNA damage can contribute to astrocyte dysfunction in neurodegenerative diseases has recently emerged from the study of astrocytes from Huntington's Disease patients (Lange et al, 2023). Perturbation of nuclear SOD1 functions is also expected to contribute to enhanced astrocyte reactivation.…”

Section: Discussionmentioning

confidence: 99%

Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients withSOD1mutations

Soubannier,

Chaineau,

Gursu

et al. 2023

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the progressive death of motor neurons (MNs). MN degeneration in ALS involves both cell-autonomous and non-cell autonomous mechanisms, with glial cells playing important roles in the latter. More specifically, astrocytes with mutations in the ALS-associated geneCu/Zn superoxide dismutase 1(SOD1) promote MN death. The mechanisms by whichSOD1-mutated astrocytes reduce MN survival are incompletely understood. In order to characterize the impact ofSOD1mutations on astrocyte physiology, we generated astrocytes from human induced pluripotent stem cell (iPSC) derived from ALS patients carryingSOD1mutations, together with control isogenic iPSCs. We report that astrocytes harbouringSOD1(A4V) andSOD1(D90A) mutations exhibit molecular and morphological changes indicative of reactive astrogliosis when compared to matching isogenic astrocytes. We show further that a number of nuclear phenotypes precede, or coincide with, reactive transformation. These include increased nuclear oxidative stress and DNA damage, and accumulation of the SOD1 protein in the nucleus. These findings reveal early cell-autonomous phenotypes inSOD1-mutated astrocytes that may contribute to the acquisition of a reactive phenotype involved in alterations of astrocyte-MN communication in ALS.

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Section: Discussionmentioning

confidence: 99%

Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients withSOD1mutations

Soubannier,

Chaineau,

Gursu

et al. 2023

Preprint

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“…There is evidence supporting the correlation between HD and metabolic dysregulation, potentiating the impact of metabolic modulators in the treatment of HD [35][36][37]. This dysregulation affects the metabolism of tricarboxylic acids, urea, amino acids, and lactate [38].…”

Section: Overview Of Evidence Supporting Use Of Metformin In Hdmentioning

confidence: 96%

Huntington’s Disease Drug Development: A Phase 3 Pipeline Analysis

Van de Roovaart,

Nguyen,

Veenstra

2023

Pharmaceuticals

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Huntington’s Disease (HD) is a severely debilitating neurodegenerative disorder in which sufferers exhibit different combinations of movement disorders, dementia, and behavioral or psychiatric abnormalities. The disorder is a result of a trinucleotide repeat expansion mutation that is inherited in an autosomal dominant manner. While there is currently no treatment to alter the course of HD, there are medications that lessen abnormal movement and psychiatric symptoms. ClinicalTrials.gov was searched to identify drugs that are currently in or have completed phase III drug trials for the treatment of HD. The described phase III trials were further limited to interventional studies that were recruiting, active not recruiting, or completed. In addition, all studies must have posted an update within the past year. PubMed was used to gather further information on these interventional studies. Of the nine clinical trials that met these criteria, eight involved the following drugs: metformin, dextromethorphan/quinidine, deutetrabenazine, valbenazine, Cellavita HD, pridopidine, SAGE-718, and RO7234292 (RG6042). Of these drug treatments, four are already FDA approved. This systematic review provides a resource that summarizes the present therapies for treating this devastating condition that are currently in phase III clinical trials in the United States.

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“…The development of Huntington’s Disease (HD) has been attributed to an increase in astrocyte dysfunction; however, the potential metabolic mechanisms within this association were unclear prior to Lange et al’s work [ 61 ]. Lange and colleagues explored the connections between polyQ length and gene expression and the overall damage response within astrocytes to see if a significant relationship in either condition exists [ 61 ].…”

Section: Common Metabolic Dysfunctions In Polyglutamine Diseasesmentioning

confidence: 99%

Altered Metabolic Signaling and Potential Therapies in Polyglutamine Diseases

Vohra,

Keefe,

Puthanveetil

2024

Metabolites

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Polyglutamine diseases comprise a cluster of genetic disorders involving neurodegeneration and movement disabilities. In polyglutamine diseases, the target proteins become aberrated due to polyglutamine repeat formation. These aberrant proteins form the root cause of associated complications. The metabolic regulation during polyglutamine diseases is not well studied and needs more attention. We have brought to light the significance of regulating glutamine metabolism during polyglutamine diseases, which could help in decreasing the neuronal damage associated with excess glutamate and nucleotide generation. Most polyglutamine diseases are accompanied by symptoms that occur due to excess glutamate and nucleotide accumulation. Along with a dysregulated glutamine metabolism, the Nicotinamide adenine dinucleotide (NAD+) levels drop down, and, under these conditions, NAD+ supplementation is the only achievable strategy. NAD+ is a major co-factor in the glutamine metabolic pathway, and it helps in maintaining neuronal homeostasis. Thus, strategies to decrease excess glutamate and nucleotide generation, as well as channelizing glutamine toward the generation of ATP and the maintenance of NAD+ homeostasis, could aid in neuronal health. Along with understanding the metabolic dysregulation that occurs during polyglutamine diseases, we have also focused on potential therapeutic strategies that could provide direct benefits or could restore metabolic homeostasis. Our review will shed light into unique metabolic causes and into ideal therapeutic strategies for treating complications associated with polyglutamine diseases.

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PolyQ length-dependent metabolic alterations and DNA damage drive human astrocyte dysfunction in Huntington’s disease

Cited by 9 publications

References 90 publications

Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients withSOD1mutations

Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients withSOD1mutations

Huntington’s Disease Drug Development: A Phase 3 Pipeline Analysis

Altered Metabolic Signaling and Potential Therapies in Polyglutamine Diseases

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