PMC:6610326 / 39639-41527
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6610326","sourcedb":"PMC","sourceid":"6610326","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6610326","text":"The expression of specific proteins can vary between MN subpopulations and this may be linked to their vulnerability to degenerate. Evidence for this hypothesis comes from the existing mouse models of ALS. Whilst mutant SOD1G93A is expressed in all MNs in these mice (Jaarsma et al., 2008), its propensity to induce neurodegeneration and disease is proportional to its expression level (Table 6) (Gurney et al., 1994; Bruijn et al., 1997; Alexander et al., 2004). At lower levels of expression, pathology is restricted to MNs in the spinal cord and brainstem only, whereas higher expression levels also induce severe abnormalities in the brain. Fewer copies of the SOD1G37R transgene correlate with delayed disease progression and a significant increase in lifespan compared to animals with higher copy numbers (Table 6) (Zwiegers et al., 2014). Similarly, in TDP-43 models, higher levels of overexpression are associated with a worse phenotype (Philips and Rothstein, 2015). Moreover, disease is evident in both wildtype and mutant TDP-43 models, indicating that the expression levels of TDP-43, rather than the presence of a mutation per se, induces neurodegeneration. Hence, the effect of the TDP-43 mutation can be difficult to segregate from the effects of overexpression in these models (Philips and Rothstein, 2015). Both retaining the physiological expression levels and normal nuclear localization of TDP-43 have been linked to maintaining cellular homeostasis (Swarup et al., 2011; Philips and Rothstein, 2015). These studies together highlight the role of differing protein expression levels in the development and progression of ALS. However, further work is required to determine whether the expression levels of mutant ALS-associated proteins are different among MN subtypes, and whether this can differentially sensitize specific MNs to neurodegeneration and stress in ALS.","tracks":[{"project":"2_test","denotations":[{"id":"31316328-18305242-38515537","span":{"begin":284,"end":288},"obj":"18305242"},{"id":"31316328-8209258-38515538","span":{"begin":412,"end":416},"obj":"8209258"},{"id":"31316328-9052802-38515539","span":{"begin":433,"end":437},"obj":"9052802"},{"id":"31316328-15519671-38515540","span":{"begin":457,"end":461},"obj":"15519671"},{"id":"31316328-25103619-38515541","span":{"begin":839,"end":843},"obj":"25103619"},{"id":"31316328-26344214-38515542","span":{"begin":969,"end":973},"obj":"26344214"},{"id":"31316328-26344214-38515543","span":{"begin":1317,"end":1321},"obj":"26344214"},{"id":"31316328-22084410-38515544","span":{"begin":1486,"end":1490},"obj":"22084410"},{"id":"31316328-26344214-38515545","span":{"begin":1515,"end":1519},"obj":"26344214"}],"attributes":[{"subj":"31316328-18305242-38515537","pred":"source","obj":"2_test"},{"subj":"31316328-8209258-38515538","pred":"source","obj":"2_test"},{"subj":"31316328-9052802-38515539","pred":"source","obj":"2_test"},{"subj":"31316328-15519671-38515540","pred":"source","obj":"2_test"},{"subj":"31316328-25103619-38515541","pred":"source","obj":"2_test"},{"subj":"31316328-26344214-38515542","pred":"source","obj":"2_test"},{"subj":"31316328-26344214-38515543","pred":"source","obj":"2_test"},{"subj":"31316328-22084410-38515544","pred":"source","obj":"2_test"},{"subj":"31316328-26344214-38515545","pred":"source","obj":"2_test"}]},{"project":"0_colil","denotations":[{"id":"31316328-18305242-630994","span":{"begin":284,"end":288},"obj":"18305242"},{"id":"31316328-8209258-630995","span":{"begin":412,"end":416},"obj":"8209258"},{"id":"31316328-9052802-630996","span":{"begin":433,"end":437},"obj":"9052802"},{"id":"31316328-15519671-630997","span":{"begin":457,"end":461},"obj":"15519671"},{"id":"31316328-25103619-630998","span":{"begin":839,"end":843},"obj":"25103619"},{"id":"31316328-26344214-630999","span":{"begin":969,"end":973},"obj":"26344214"},{"id":"31316328-26344214-631000","span":{"begin":1317,"end":1321},"obj":"26344214"},{"id":"31316328-22084410-631001","span":{"begin":1486,"end":1490},"obj":"22084410"},{"id":"31316328-26344214-631002","span":{"begin":1515,"end":1519},"obj":"26344214"}],"attributes":[{"subj":"31316328-18305242-630994","pred":"source","obj":"0_colil"},{"subj":"31316328-8209258-630995","pred":"source","obj":"0_colil"},{"subj":"31316328-9052802-630996","pred":"source","obj":"0_colil"},{"subj":"31316328-15519671-630997","pred":"source","obj":"0_colil"},{"subj":"31316328-25103619-630998","pred":"source","obj":"0_colil"},{"subj":"31316328-26344214-630999","pred":"source","obj":"0_colil"},{"subj":"31316328-26344214-631000","pred":"source","obj":"0_colil"},{"subj":"31316328-22084410-631001","pred":"source","obj":"0_colil"},{"subj":"31316328-26344214-631002","pred":"source","obj":"0_colil"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93adec","default":true},{"id":"0_colil","color":"#c7ec93"}]}]}}