We tested this hypothesis using a polyglutamine protein aggregation model, where polyQ35 proteins in muscles form aggregates in an age-dependent manner and the onset and severity of polyQ35 aggregation serve as a proxy for protein homeostasis (Garcia SM et al. Genes Dev, 2007, 21 3006).
However, a significant inverse correlation was observed between the level of phospho-NBR1T586 and the severity of protein aggregation, meaning that among sIBM patients, the level of remaining NBR1 phosphorylation is a direct readout of protein aggregation (Fig. 5D).
Indeed, we have shown that NBR1 phosphorylation is strongly decreased in muscles of sIBM patients and directly correlates with the severity of protein aggregation in these patients.
Analysis of muscle biopsies of sporadic inclusion body myositis (sIBM) patients revealed a strong decrease of NBR1 phosphorylation in muscles of sIBM patients that directly correlated with the severity of protein aggregation.
Consistently, we have observed a strong reduction of NBR1 phosphorylation in muscles of sIBM patients, and residual levels of phospho-NBR1T586 in sIBM patients directly correlated with the severity of protein aggregation.
Scores were assigned to each patient on a scale from 0 to 3 (0 for the absence of the symptom, 3 for the most severe) to evaluate the severity of 4 typical sIBM symptoms: protein aggregation, inflammation, necrosis, fibrosis (Table S1).
These results would be predicted by the correlation of aggregation propensity with disease severity, as would the minimal aggregation of SOD1 containing the G37R substitution, which causes relatively slowly progressing paralysis in ALS patients and mouse models.
These findings validate the importance of aggregation kinetics in modulating the severity of polyglutamine-mediated neuronal dysfunction.
The study tested the primary hypothesis that whole blood aggregation of platelets from patients with septic shock would be attenuated and that the degree of aggregation impairment would correlate with illness severity indexed by the SOFA and APACHE II scores.
