Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte
and Microglia

Saba, Julieta; Couselo, Federico López; Bruno, Julieta; Carniglia, Lila; Durand, Daniela Elizabeth; Lasaga, Mercedes; Caruso, Carla Mariana

doi:10.2174/1570159x19666211201094608

Cited by 50 publications

(26 citation statements)

References 296 publications

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“…Consequently, having the ability to quickly validate potential gene modifiers that can regulate the kinetics of repeat expansion progression associated with RE disorders in a cell-based assay would be very valuable. Here, we describe developing a new RE cell-based system by leveraging stem cell technology to differentiate HD patient iPSC into astrocytes, a cell type in the CNS is highly correlated to the pathology of RE disorders (58)(59)(60). Our HD iPSC-derived astrocyte platform displays the expanded CAG repeats within six weeks and is characterized by a robust/exponential increase of repeat instability (Fig.…”

Section: Discussionmentioning

confidence: 99%

Increased FAN1 expression by mRNA-LNP attenuates CAG repeat expansion in Huntington patients’ iPSC-derived astrocytes

Cheng,

Nocula-Lugowska,

Ramirez

et al. 2023

Preprint

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Expansion of repeat sequences within the human genome can lead to disease pathogenesis, such as Huntington’s Disease, primarily affecting the nervous system. Genome-wide association studies (GWAS) of age-at-onset in Huntington’s disease (HD) patients demonstrated DNA mismatch repair (MMR) genes are modifiers of somatic expansion and may be potential therapeutic targets for repeat expansion (RE) disorders. FAN1, a Fanconi anemia-associated nuclease, has been reported as an influencer of repeat expansion in the RE mouse models. Here, we show the first demonstration that FAN1 knock-out in HD patient-derived fibroblasts and results in increased CAG repeat length. We also develop a robust novel cell-based platform using stem cell technology to produce the HD patients’ iPSC-derived astrocytes (iAstro). This platform is a disease-relevant system and has a significantly wider assay window, making it more suitable to assess the effect of gene modulation on CAG repeats. A substantial and exponential increase in repeat instability was exhibited in this HD patient’s iPSC-derived astrocytes platform. Over-expression of FAN1 protein viaFAN1plasmid transfection in this platform reduced CAG repeat instability, suggesting that upregulation of FAN1 protein may have a potential protective effect in CAG repeat expansion for a therapeutic setting. We leveraged the mRNA-LNP modality to enhance FAN1 protein expression and revealed that codon-optimizedFAN1mRNA-LNP robustly prevented increased CAG repeat in HD patients’ iPSC-derived astrocytes platform. The data from these cell-based platforms highlight that FAN1 plays a protective role in attenuating expanded somaticHTTCAG repeats and shed light on new therapeutic directions against repeat expansion disorders.

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Section: Discussionmentioning

confidence: 99%

Increased FAN1 expression by mRNA-LNP attenuates CAG repeat expansion in Huntington patients’ iPSC-derived astrocytes

Cheng,

Nocula-Lugowska,

Ramirez

et al. 2023

Preprint

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“…Although its primary role is to initiate the chain of molecular and cellular events to restore disturbed homeostasis, prolonged inflammation has detrimental effects on body functioning. Inflammatory response within the brain or spinal cord, called neuroinflammation, is considered a crucial component of neurodegenerative diseases [ 106 , 107 , 108 , 109 , 110 ]; hence knowledge about the role of SPL in neuroinflammation may help understand the molecular basis of neurodegeneration.…”

Section: Spl In Neuroinflammationmentioning

confidence: 99%

Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration

Wieczorek

Strosznajder

2023

IJMS

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Sphingosine-1-phosphate lyase (SPL) is a pyridoxal 5′-phosphate-dependent enzyme involved in the irreversible degradation of sphingosine-1-phosphate (S1P)—a bioactive sphingolipid that modulates a broad range of biological processes (cell proliferation, migration, differentiation and survival; mitochondrial functioning; and gene expression). Although SPL activity leads to a decrease in the available pool of S1P in the cell, at the same time, hexadecenal and phosphoethanolamine, compounds with potential biological activity, are generated. The increased expression and/or activity of SPL, and hence the imbalance between S1P and the end products of its cleavage, were demonstrated in several pathological states. On the other hand, loss-of-function mutations in the SPL encoding gene are a cause of severe developmental impairments. Recently, special attention has been paid to neurodegenerative diseases as the most common pathologies of the nervous system. This review summarizes the current findings concerning the role of SPL in the nervous system with an emphasis on neurodegeneration. Moreover, it briefly discusses pharmacological compounds directed to inhibit its activity.

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“…Neuroinflammation has been increasingly shown to contribute to neuronal damage in Alzheimer’s disease [ 215 ], Parkinson’s disease [ 216 ], amyotrophic lateral sclerosis [ 40 ], stroke [ 41 ], as well as in Huntington’s disease [ 217 ]. Expression and accumulation of mHtt in neurons, as well as in microglia, have been implicated in microglial activation and ignition of the neuroinflammatory cascade [ 218 ].…”

Section: Therapeutic Strategies In Huntington’s Diseasementioning

confidence: 99%

Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

Jurcău

2022

Biomedicines

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Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for “gene editing”. Although some issues relating to “off-target” effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington’s disease patients.

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Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia

Cited by 50 publications

References 296 publications

Increased FAN1 expression by mRNA-LNP attenuates CAG repeat expansion in Huntington patients’ iPSC-derived astrocytes

Increased FAN1 expression by mRNA-LNP attenuates CAG repeat expansion in Huntington patients’ iPSC-derived astrocytes

Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration

Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

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