Garage Brain Science

The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is based mainly on clinical presentations, and the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NETs) to investigate axonal membrane properties and chemical precipitation, followed by ELISA analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-voltage threshold curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the current-voltage threshold curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72 or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely to be associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the current-voltage threshold curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partly prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes to familial ALS patients and ALS mice with mutant SOD1, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the current-voltage threshold curve was attributable to an elevation in the HCN current in SOD1-associated ALS.

Abstract While therapies like Spinraza, Zolgensma, and Evrysdi focus on increasing SMN1 protein levels to treat spinal muscular atrophy (SMA), their effectiveness is limited and highly dependent on early intervention. This indicates that merely augmenting SMN levels may not adequately reverse the permanent pathological effects stemming from SMN1 deficiency. Our research indicates that SMA is a protein conformational disorder rather than solely a splicing disease. We found that the SMN protein contains prion-like domains located in exon 2 and exons 6-7. Due to the absence of exon 7, the SMNΔ7 variant displays reduced prion-like activity. This deficit hampers gemins and RNPs formation and leading to persistent misfolded TDP-43 and PFN1 proteins despite treatment with Spinraza and Evrysdi. Remarkably, treatment with baicalein, a prion-like folding stabilizer, enabled SMNΔ7 to form a prion-like structure, restored the assembly of gemins and RNPs, effectively cleared toxic aggregated TDP-43 proteins and alleviated symptoms in SMA models.

Abstract A group of misfolded prone-to-aggregate domains in disease-causing proteins has recently been shown to adopt unique conformations that play a role in fundamental biological processes, including the formation of membrane-less sub-organelles, alternative splicing, and gene activation. The cellular responses are regulated by the conformational switching of prone-to-aggregate domains. Given this, targeting the misfolded states of disease-causing proteins to redirect them towards their physiological conformations is emerging as an effective therapeutic strategy for diseases caused by protein misfolding. In our study, we successfully identified baicalein as a potent structure-correcting agent. Our findings demonstrate that baicalein can reconfigure existing TDP-43 aggregates into an oligomeric state both in vitro and in disease cells. This transformation effectively restores the bioactivity of misfolded TDP-43 proteins in cellular models of ALS and premature aging in progeria. Impressively, in progeria cells where defective lamin A interferes with TDP-43-mediated exon skipping, the formation of pathological TDP-43 aggregates is promoted. Baicalein, however, restores the functionality of TDP-43 and mitigates nuclear shape defects in these laminopathic cells. This establishes a connection between lamin A and TDP-43 in the context of aging. Our findings suggest that targeting physiological TDP-43 oligomers could offer a promising therapeutic avenue for treating aging-associated disorders.