Huntingtin Aggregation Impairs Autophagy, Leading to Argonaute-2 Accumulation and Global MicroRNA Dysregulation

Pircs, Karolina; Petri, Rebecca; Madsen, Sofia; Brattås, Per Ludvik; Vuono, Romina; Ottosson, Daniella Rylander; St‐Amour, Isabelle; Hersbach, Bob A.; Matusiak-Brückner, Monika; Lundh, Sofia; Petersén, Åsa; Déglon, Nicole; Hébert, Sébastien S.; Parmar, Malin; Barker, Roger A.; Jakobsson, Johan

doi:10.1016/j.celrep.2018.07.017

Cited by 76 publications

(84 citation statements)

References 26 publications

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“…4 A and B ). This finding indicates that the steady-state basal autophagy levels are higher in HD cells than in control cells, as reported in previous studies ( 56 – 58 ).…”

Section: Resultssupporting

confidence: 90%

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Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Sharma

Sumitha

Shahani

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

106

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Huntington disease (HD) is caused by an expansion mutation of the N-terminal polyglutamine of huntingtin (mHTT). mHTT is ubiquitously present, but it induces noticeable damage to the brain’s striatum, thereby affecting motor, psychiatric, and cognitive functions. The striatal damage and progression of HD are associated with the inflammatory response; however, the underlying molecular mechanisms remain unclear. Here, we report that cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling revealed that thecGASmRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. Moreover, the protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5andCxcl10) are increased in HD striatum. Depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the up-regulation of autophagy in HD cells. In contrast, reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Ribosome profiling also revealed thatLC3AandLC3B, the two major autophagy initiators, show altered ribosome occupancy in HD cells. We also detected the presence of numerous micronuclei, which are known to induce cGAS, in the cytoplasm of neurons derived from human HD embryonic stem cells. Collectively, our results indicate that cGAS is up-regulated in HD and mediates inflammatory and autophagy responses. Thus, targeting the cGAS pathway may offer therapeutic benefits in HD.

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“…4 A and B ). This finding indicates that the steady-state basal autophagy levels are higher in HD cells than in control cells, as reported in previous studies ( 56 – 58 ).…”

Section: Resultssupporting

confidence: 90%

“…Next, we investigated whether cGAS modulates autophagy flux in HD, as previous studies suggest that HD cells show enhanced autophagy flux as well as cargo-loading defects ( 56 , 58 , 60 ). We treated cGASΔ-HD-homo cells and control cells with chloroquine (CQ), which is a known inhibitor of autophagy flux ( 61 , 62 ).…”

Section: Resultsmentioning

confidence: 99%

Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Sharma

Sumitha

Shahani

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

106

View full text Add to dashboard Cite

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“…In either case, however, the problem lies in the accumulation of the protein. Evidence supports the view that protein aggregates are removed by autophagy [12,13,14,15,16,17,18,19,20]. Moreover, there is good evidence that enhancing autophagy is beneficial for treating neurodegenerative diseases [13,14,15,17,21].…”

Section: Proteinopathy and Autophagymentioning

confidence: 72%

Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?

Mehta

Marwah

Njus

2019

Cells

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Parkinson’s disease, like other neurodegenerative diseases, exhibits two common features: Proteinopathy and oxidative stress, leading to protein aggregation and mitochondrial damage respectively. Because both protein aggregates and dysfunctional mitochondria are eliminated by autophagy, we suggest that inadequate clearance may couple the two phenomena. If a neuron’s autophagy machinery is overwhelmed, whether by excessive oxidative stress or by excessive protein aggregation, protein aggregates and dysfunctional mitochondria will both accumulate. Parkinson’s disease may provide a unique window into this because there is evidence that both sides contribute. Mutations amplifying the aggregation of α-synuclein are associated with Parkinson’s disease. Likewise, mutations in Parkin and PINK1, proteins involved in mitophagy, suggest that impaired mitochondrial clearance is also a contributing factor. Many have suggested that dopamine oxidation products lead to oxidative stress accounting for the dopaminergic selectivity of the disease. We have presented evidence for the specific involvement of hypochlorite-oxidized cysteinyl-dopamine (HOCD), a redox-cycling benzothiazine derivative. While toxins like 6-hydroxydopamine and 1-methyl-4-phenyl pyridinium (MPP+) have been used to study mitochondrial involvement in Parkinson’s disease, HOCD may provide a more physiologically relevant approach. Understanding the role of mitochondrial dysfunction and oxidative stress in Parkinson’s disease and their relation to α-synuclein proteinopathy is important to gain a full picture of the cause, especially for the great majority of cases which are idiopathic.

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“…Although the effect of the isomiRs is uncertain, the perturbations of those involving the seed region of the miRNA may likely vary the gene targeting profile, thus increasing the complexity in the miRNA depending effects. The strong perturbations in miRNA expression described in HD could be explained, at least in part, by the accumulation of AGO2 in aggregates [214], through a mechanism involving impaired autophagy [215]. AGO2 is a major executor of the miRNA-mediated gene silencing, and its accumulation in HTT-aggregates results in abnormal miRNA activity and expression levels.…”

Section: Huntington's Diseasementioning

confidence: 99%

Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

et al. 2020

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Oxidative stress (OS) results from an imbalance between the production of reactive oxygen species and the cellular antioxidant capacity. OS plays a central role in neurodegenerative diseases, where the progressive accumulation of reactive oxygen species induces mitochondrial dysfunction, protein aggregation and inflammation. Regulatory non-protein-coding RNAs (ncRNAs) are essential transcriptional and post-transcriptional gene expression controllers, showing a highly regulated expression in space (cell types), time (developmental and ageing processes) and response to specific stimuli. These dynamic changes shape signaling pathways that are critical for the developmental processes of the nervous system and brain cell homeostasis. Diverse classes of ncRNAs have been involved in the cell response to OS and have been targeted in therapeutic designs. The perturbed expression of ncRNAs has been shown in human neurodegenerative diseases, with these changes contributing to pathogenic mechanisms, including OS and associated toxicity. In the present review, we summarize existing literature linking OS, neurodegeneration and ncRNA function. We provide evidences for the central role of OS in age-related neurodegenerative conditions, recapitulating the main types of regulatory ncRNAs with roles in the normal function of the nervous system and summarizing up-to-date information on ncRNA deregulation with a direct impact on OS associated with major neurodegenerative conditions.

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Huntingtin Aggregation Impairs Autophagy, Leading to Argonaute-2 Accumulation and Global MicroRNA Dysregulation

Cited by 76 publications

References 26 publications

Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?

Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

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