Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy

Oh, Young Mi; Lee, Seong Won; Kim, Woo Kyung; Chen, Shawei; Church, Victoria A.; Cates, K. Lynn; Li, Tiandao; Zhang, Bo; Dolle, Roland E.; Dahiya, Sonika; Pak, Stephen C.; Silverman, Gary A.; Perlmutter, David H.; Yoo, Andrew S.

doi:10.1038/s41593-022-01185-4

Cited by 58 publications

(56 citation statements)

References 57 publications

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“…This interaction also decreases the solubility of the toxic mHTT protein and its association with SQSTM1 ( Ramírez-Jarquín et al, 2022 ). Additionally, a recent finding from Oh et al (2022) reported that human fibroblasts directly reprogrammed to medium spiny neurons from HD patients show impairments in functional autophagy. Specifically, the authors identified an aging-associated upregulation of a microRNA (miR-29b-3p) that contributes to degeneration by targeting the human STAT3 3’ untranslated region, which is relevant for functional autophagy ( You et al, 2015 ).…”

Section: Autophagy and Autophagic Lysosome Reformation (Alr) Impairme...mentioning

confidence: 99%

Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

Diab

Pilotto

Saxena

2023

Front. Cell. Neurosci.

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The proper functioning of the cell clearance machinery is critical for neuronal health within the central nervous system (CNS). In normal physiological conditions, the cell clearance machinery is actively involved in the elimination of misfolded and toxic proteins throughout the lifetime of an organism. The highly conserved and regulated pathway of autophagy is one of the important processes involved in preventing and neutralizing pathogenic buildup of toxic proteins that could eventually lead to the development of neurodegenerative diseases (NDs) such as Alzheimer’s disease or Amyotrophic lateral sclerosis (ALS). The most common genetic cause of ALS and frontotemporal dementia (FTD) is a hexanucleotide expansion consisting of GGGGCC (G4C2) repeats in the chromosome 9 open reading frame 72 gene (C9ORF72). These abnormally expanded repeats have been implicated in leading to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs). In this review, we discuss the normal physiological role of C9ORF72 in the autophagy-lysosome pathway (ALP), and present recent research deciphering how dysfunction of the ALP synergizes with C9ORF72 haploinsufficiency, which together with the gain of toxic mechanisms involving hexanucleotide repeat expansions and DPRs, drive the disease process. This review delves further into the interactions of C9ORF72 with RAB proteins involved in endosomal/lysosomal trafficking, and their role in regulating various steps in autophagy and lysosomal pathways. Lastly, the review aims to provide a framework for further investigations of neuronal autophagy in C9ORF72-linked ALS-FTD as well as other neurodegenerative diseases.

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Section: Autophagy and Autophagic Lysosome Reformation (Alr) Impairme...mentioning

confidence: 99%

Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

Diab

Pilotto

Saxena

2023

Front. Cell. Neurosci.

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“…PERK pathway activation causes transient protein synthesis inhibition, reducing ER protein load, and inducing cell protective pathways through eIF2α phosphorylation which increases ATF4 expression and by direct phosphorylation and activation of NRF2 [6,7]. PERK activation also stimulates autophagy, which has important neuroprotective effects in HD [24,25].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of therapy by MK-28 PERK activation in the Huntington's disease R6/2 mouse model

Shacham

Offen

Lederkremer

2023

Preprint

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There is currently no disease-modifying therapy for Huntington’s disease (HD) and two recent clinical trials testing antisense oligonucleotides failed. We recently described a small molecule, MK-28, which restored homeostasis in HD models by specifically activating PKR‐like ER kinase (PERK) and thus boosting neuroprotection by the unfolded protein response (UPR), and reducing endoplasmic reticulum (ER) stress, a central cytotoxic mechanism in HD and other neurodegenerative diseases. Here we have tested the long-term effects of MK-28 in HD model mice. R6/2 CAG (160) mice were treated by lifetime IP injection, 3 times a week. CatWalk measurements of motor function showed significant improvement after only two weeks of MK-28 treatment and continued with time, most significantly at 1 mg/kg MK-28, approaching WT values. Seven weeks treatment significantly improved paw grip strength. Body weight recovered and glucose levels, which are elevated in HD mice, were significantly lowered. Treatment with another PERK activator, CCT020312, also caused amelioration, although less significant than with MK-28 in some of the parameters. Lifespan, measured in more resilient R6/2 CAG (120) mice with daily IP injection, was significantly extended by 16 days (20%) with 0.3 mg/kg MK-28, and by 38 days (46%) with 1 mg/kg MK-28. No toxicity, measured by weight, blood glucose levels and blood liver function markers, was detectable in WT mice treated for 6 weeks with 6 mg/kg MK-28. Boosting of PERK activity by long-term treatment with MK-28 appears to be a safe and promising therapeutic approach for HD.

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“…Most interestingly, immunocytochemistry staining of autophagic structures (LC3B, p62, and LAMP1) clearly showed that there is a subcellular, compartment-specific impairment of autophagy in HD-iNs characterized by autophagosome accumulation in the neurites ( Pircs et al, 2022 ). Oh et al (2022) used HD-derived induced medium spiny neurons (iMSNs) generated from healthy donors, symptomatic (HD-iMSNs) and pre-symptomatic HD (preHD-iMSNs) patients using direct reprogramming. They found remarkable age- and disease-related alterations in chromatin accessibility, decrease in LC3B + and increase in p62 + autophagic structures and miR-29b-3p miRNA upregulation in HD-iMSNs compared to the control and preHD-iMSN groups ( Oh et al, 2022 ).…”

Section: Cellular Reprogramming Models To Study Autophagymentioning

confidence: 99%

“… Oh et al (2022) used HD-derived induced medium spiny neurons (iMSNs) generated from healthy donors, symptomatic (HD-iMSNs) and pre-symptomatic HD (preHD-iMSNs) patients using direct reprogramming. They found remarkable age- and disease-related alterations in chromatin accessibility, decrease in LC3B + and increase in p62 + autophagic structures and miR-29b-3p miRNA upregulation in HD-iMSNs compared to the control and preHD-iMSN groups ( Oh et al, 2022 ). Target gene pathway analysis of miR-29b-3p revealed the role of miR-29b-3p in senescence and autophagy ( Oh et al, 2022 ).…”

Section: Cellular Reprogramming Models To Study Autophagymentioning

confidence: 99%

Fountain of youth—Targeting autophagy in aging

Danics

Abbas

Kis

et al. 2023

Front. Aging Neurosci.

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As our society ages inexorably, geroscience and research focusing on healthy aging is becoming increasingly urgent. Macroautophagy (referred to as autophagy), a highly conserved process of cellular clearance and rejuvenation has attracted much attention due to its universal role in organismal life and death. Growing evidence points to autophagy process as being one of the key players in the determination of lifespan and health. Autophagy inducing interventions show significant improvement in organismal lifespan demonstrated in several experimental models. In line with this, preclinical models of age-related neurodegenerative diseases demonstrate pathology modulating effect of autophagy induction, implicating its potential to treat such disorders. In humans this specific process seems to be more complex. Recent clinical trials of drugs targeting autophagy point out some beneficial effects for clinical use, although with limited effectiveness, while others fail to show any significant improvement. We propose that using more human-relevant preclinical models for testing drug efficacy would significantly improve clinical trial outcomes. Lastly, the review discusses the available cellular reprogramming techniques used to model neuronal autophagy and neurodegeneration while exploring the existing evidence of autophagy’s role in aging and pathogenesis in human-derived in vitro models such as embryonic stem cells (ESCs), induced pluripotent stem cell derived neurons (iPSC-neurons) or induced neurons (iNs).

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Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy

Cited by 58 publications

References 57 publications

Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

Efficacy of therapy by MK-28 PERK activation in the Huntington's disease R6/2 mouse model

Fountain of youth—Targeting autophagy in aging

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