ALS’ Perfect Storm: <i>C9orf72</i>-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis
Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin–proteasome systems, maintains protein homeostasis in neurons, which are post-m...
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| Format: | Article |
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MDPI AG
2024-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/13/2/178 |
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| author | Paulien H. Smeele Giuliana Cesare Thomas Vaccari |
| author_facet | Paulien H. Smeele Giuliana Cesare Thomas Vaccari |
| author_sort | Paulien H. Smeele |
| collection | DOAJ |
| description | Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin–proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell division to diminish the burden of misfolded proteins. When protein clearance pathways are overwhelmed or otherwise disrupted, the accumulation of misfolded or aggregated proteins can lead to the activation of ER stress and the formation of stress granules, which predominantly attempt to restore the homeostasis by suppressing global protein translation. Alterations in these processes have been widely reported among studies investigating the toxic function of dipeptide repeats (DPRs) produced by G4C2 expansion in the C9orf72 gene of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review, we outline the modalities of DPR-induced disruptions in protein homeostasis observed in a wide range of models of C9orf72-linked ALS/FTD. We also discuss the relative importance of each DPR for toxicity, possible synergies between DPRs, and discuss the possible functional relevance of DPR aggregation to disease pathogenesis. Finally, we highlight the interdependencies of the observed effects and reflect on the importance of feedback and feedforward mechanisms in their contribution to disease progression. A better understanding of DPR-associated disease pathogenesis discussed in this review might shed light on disease vulnerabilities that may be amenable with therapeutic interventions. |
| first_indexed | 2024-03-08T09:56:18Z |
| format | Article |
| id | doaj.art-e3fec9a510fb4e05acc4280c38c51d9a |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-08T09:56:18Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e3fec9a510fb4e05acc4280c38c51d9a2024-01-29T13:50:34ZengMDPI AGCells2073-44092024-01-0113217810.3390/cells13020178ALS’ Perfect Storm: <i>C9orf72</i>-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein HomeostasisPaulien H. Smeele0Giuliana Cesare1Thomas Vaccari2Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milan, ItalyDepartment of Biosciences, University of Milan, Via Celoria 26, 20133 Milan, ItalyDepartment of Biosciences, University of Milan, Via Celoria 26, 20133 Milan, ItalyProtein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin–proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell division to diminish the burden of misfolded proteins. When protein clearance pathways are overwhelmed or otherwise disrupted, the accumulation of misfolded or aggregated proteins can lead to the activation of ER stress and the formation of stress granules, which predominantly attempt to restore the homeostasis by suppressing global protein translation. Alterations in these processes have been widely reported among studies investigating the toxic function of dipeptide repeats (DPRs) produced by G4C2 expansion in the C9orf72 gene of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review, we outline the modalities of DPR-induced disruptions in protein homeostasis observed in a wide range of models of C9orf72-linked ALS/FTD. We also discuss the relative importance of each DPR for toxicity, possible synergies between DPRs, and discuss the possible functional relevance of DPR aggregation to disease pathogenesis. Finally, we highlight the interdependencies of the observed effects and reflect on the importance of feedback and feedforward mechanisms in their contribution to disease progression. A better understanding of DPR-associated disease pathogenesis discussed in this review might shed light on disease vulnerabilities that may be amenable with therapeutic interventions.https://www.mdpi.com/2073-4409/13/2/178protein homeostasisALSFTD<i>C9orf72</i>dipeptide repeatsautophagy |
| spellingShingle | Paulien H. Smeele Giuliana Cesare Thomas Vaccari ALS’ Perfect Storm: <i>C9orf72</i>-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis Cells protein homeostasis ALS FTD <i>C9orf72</i> dipeptide repeats autophagy |
| title | ALS’ Perfect Storm: <i>C9orf72</i>-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis |
| title_full | ALS’ Perfect Storm: <i>C9orf72</i>-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis |
| title_fullStr | ALS’ Perfect Storm: <i>C9orf72</i>-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis |
| title_full_unstemmed | ALS’ Perfect Storm: <i>C9orf72</i>-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis |
| title_short | ALS’ Perfect Storm: <i>C9orf72</i>-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis |
| title_sort | als perfect storm i c9orf72 i associated toxic dipeptide repeats as potential multipotent disruptors of protein homeostasis |
| topic | protein homeostasis ALS FTD <i>C9orf72</i> dipeptide repeats autophagy |
| url | https://www.mdpi.com/2073-4409/13/2/178 |
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