A Meta-Analysis Study of SOD1-Mutant Mouse Models of ALS to Analyse the Determinants of Disease Onset and Progression
A complex interaction between genetic and external factors determines the development of amyotrophic lateral sclerosis (ALS). Epidemiological studies on large patient cohorts have suggested that ALS is a multi-step disease, as symptom onset occurs only after exposure to a sequence of risk factors. A...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-12-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/1/216 |
| _version_ | 1797431405736624128 |
|---|---|
| author | Maria Ciuro Maria Sangiorgio Giampiero Leanza Rosario Gulino |
| author_facet | Maria Ciuro Maria Sangiorgio Giampiero Leanza Rosario Gulino |
| author_sort | Maria Ciuro |
| collection | DOAJ |
| description | A complex interaction between genetic and external factors determines the development of amyotrophic lateral sclerosis (ALS). Epidemiological studies on large patient cohorts have suggested that ALS is a multi-step disease, as symptom onset occurs only after exposure to a sequence of risk factors. Although the exact nature of these determinants remains to be clarified, it seems clear that: (i) genetic mutations may be responsible for one or more of these steps; (ii) other risk factors are probably linked to environment and/or to lifestyle, and (iii) compensatory plastic changes taking place during the ALS etiopathogenesis probably affect the timing of onset and progression of disease. Current knowledge on ALS mechanisms and therapeutic targets, derives mainly from studies involving superoxide dismutase 1 (SOD1) transgenic mice; therefore, it would be fundamental to verify whether a multi-step disease concept can also be applied to these animal models. With this aim, a meta-analysis study has been performed using a collection of primary studies (n = 137), selected according to the following criteria: (1) the studies should employ SOD1 transgenic mice; (2) the studies should entail the presence of a disease-modifying experimental manipulation; (3) the studies should make use of Kaplan–Meier plots showing the distribution of symptom onset and lifespan. Then, using a subset of this study collection (n = 94), the effects of treatments on key molecular mechanisms, as well as on the onset and progression of disease have been analysed in a large population of mice. The results are consistent with a multi-step etiopathogenesis of disease in ALS mice (including two to six steps, depending on the particular SOD1 mutation), closely resembling that observed in patient cohorts, and revealed an interesting relationship between molecular mechanisms and disease manifestation. Thus, SOD1 mouse models may be considered of high predictive value to understand the determinants of disease onset and progression, as well as to identify targets for therapeutic interventions. |
| first_indexed | 2024-03-09T09:44:29Z |
| format | Article |
| id | doaj.art-334ee8f6a6d24c5c9017ce0b91aab4e3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T09:44:29Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-334ee8f6a6d24c5c9017ce0b91aab4e32023-12-02T00:38:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124121610.3390/ijms24010216A Meta-Analysis Study of SOD1-Mutant Mouse Models of ALS to Analyse the Determinants of Disease Onset and ProgressionMaria Ciuro0Maria Sangiorgio1Giampiero Leanza2Rosario Gulino3Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, 95123 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, 95123 Catania, ItalyDepartment of Drug and Health Sciences, University of Catania, 95125 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, 95123 Catania, ItalyA complex interaction between genetic and external factors determines the development of amyotrophic lateral sclerosis (ALS). Epidemiological studies on large patient cohorts have suggested that ALS is a multi-step disease, as symptom onset occurs only after exposure to a sequence of risk factors. Although the exact nature of these determinants remains to be clarified, it seems clear that: (i) genetic mutations may be responsible for one or more of these steps; (ii) other risk factors are probably linked to environment and/or to lifestyle, and (iii) compensatory plastic changes taking place during the ALS etiopathogenesis probably affect the timing of onset and progression of disease. Current knowledge on ALS mechanisms and therapeutic targets, derives mainly from studies involving superoxide dismutase 1 (SOD1) transgenic mice; therefore, it would be fundamental to verify whether a multi-step disease concept can also be applied to these animal models. With this aim, a meta-analysis study has been performed using a collection of primary studies (n = 137), selected according to the following criteria: (1) the studies should employ SOD1 transgenic mice; (2) the studies should entail the presence of a disease-modifying experimental manipulation; (3) the studies should make use of Kaplan–Meier plots showing the distribution of symptom onset and lifespan. Then, using a subset of this study collection (n = 94), the effects of treatments on key molecular mechanisms, as well as on the onset and progression of disease have been analysed in a large population of mice. The results are consistent with a multi-step etiopathogenesis of disease in ALS mice (including two to six steps, depending on the particular SOD1 mutation), closely resembling that observed in patient cohorts, and revealed an interesting relationship between molecular mechanisms and disease manifestation. Thus, SOD1 mouse models may be considered of high predictive value to understand the determinants of disease onset and progression, as well as to identify targets for therapeutic interventions.https://www.mdpi.com/1422-0067/24/1/216ALS epidemiologyALS pathogenesisamyotrophic lateral sclerosismathematical modelmeta-analysismouse |
| spellingShingle | Maria Ciuro Maria Sangiorgio Giampiero Leanza Rosario Gulino A Meta-Analysis Study of SOD1-Mutant Mouse Models of ALS to Analyse the Determinants of Disease Onset and Progression International Journal of Molecular Sciences ALS epidemiology ALS pathogenesis amyotrophic lateral sclerosis mathematical model meta-analysis mouse |
| title | A Meta-Analysis Study of SOD1-Mutant Mouse Models of ALS to Analyse the Determinants of Disease Onset and Progression |
| title_full | A Meta-Analysis Study of SOD1-Mutant Mouse Models of ALS to Analyse the Determinants of Disease Onset and Progression |
| title_fullStr | A Meta-Analysis Study of SOD1-Mutant Mouse Models of ALS to Analyse the Determinants of Disease Onset and Progression |
| title_full_unstemmed | A Meta-Analysis Study of SOD1-Mutant Mouse Models of ALS to Analyse the Determinants of Disease Onset and Progression |
| title_short | A Meta-Analysis Study of SOD1-Mutant Mouse Models of ALS to Analyse the Determinants of Disease Onset and Progression |
| title_sort | meta analysis study of sod1 mutant mouse models of als to analyse the determinants of disease onset and progression |
| topic | ALS epidemiology ALS pathogenesis amyotrophic lateral sclerosis mathematical model meta-analysis mouse |
| url | https://www.mdpi.com/1422-0067/24/1/216 |
| work_keys_str_mv | AT mariaciuro ametaanalysisstudyofsod1mutantmousemodelsofalstoanalysethedeterminantsofdiseaseonsetandprogression AT mariasangiorgio ametaanalysisstudyofsod1mutantmousemodelsofalstoanalysethedeterminantsofdiseaseonsetandprogression AT giampieroleanza ametaanalysisstudyofsod1mutantmousemodelsofalstoanalysethedeterminantsofdiseaseonsetandprogression AT rosariogulino ametaanalysisstudyofsod1mutantmousemodelsofalstoanalysethedeterminantsofdiseaseonsetandprogression AT mariaciuro metaanalysisstudyofsod1mutantmousemodelsofalstoanalysethedeterminantsofdiseaseonsetandprogression AT mariasangiorgio metaanalysisstudyofsod1mutantmousemodelsofalstoanalysethedeterminantsofdiseaseonsetandprogression AT giampieroleanza metaanalysisstudyofsod1mutantmousemodelsofalstoanalysethedeterminantsofdiseaseonsetandprogression AT rosariogulino metaanalysisstudyofsod1mutantmousemodelsofalstoanalysethedeterminantsofdiseaseonsetandprogression |