Russell McConnell (hailperson3)

e importance of gut biomarkers and raise interesting questions regarding the role of the gut in Huntington's disease, and whether it may be a potential target for future therapeutic intervention.Familial hypokalaemic periodic paralysis is a rare skeletal muscle disease caused by the dysregulation of sarcolemmal excitability. Hypokalaemic periodic paralysis is characterized by repeated episodes of paralytic attacks with hypokalaemia, and several variants in CACNA1S coding for CaV1.1 and SCN4A coding for NaV1.4 have been established as causative mutations. Most of the mutations are substitutions to a non-charged residue, from the positively charged arginine (R) in transmembrane segment 4 (S4) of a voltage sensor in either CaV1.1 or NaV1.4. Mutant channels have aberrant leak currents called 'gating pore currents', and the widely accepted consensus is that this current is the essential pathological mechanism that produces susceptibility to anomalous depolarization and failure of muscle excitability during a paralytic attack. Here, we have identified five hypokalaemic periodic paralysis cases from two different ethnic backgrounds, Japanese and French, with charge-preserving substitutions in S4 from arginine, R, to lysine, K. An R to K substitution has not previously been reported for any other hypokalaemic periodic paralysis families. One case is R219K in NaV1.4, which is located at the first charge in S4 of Domain I. The other four cases all have R897K in CaV1.1, which is located at the first charge in S4 of Domain III. ISX-9 order Gating pore currents were not detected in expression studies of CaV1.1-R897K. NaV1.4-R219K mutant channels revealed a distinct, but small, gating pore current. Simulation studies indicated that the small-amplitude gating pore current conducted by NaV1.4-R219K is not likely to be sufficient to be a risk factor for depolarization-induced paralytic attacks. Our rare cases with typical hypokalaemic periodic paralysis phenotypes do not fit the canonical view that the essential defect in hypokalaemic periodic paralysis mutant channels is the gating pore current and raise the possibility that hypokalaemic periodic paralysis pathogenesis might be heterogeneous and diverse.Excitotoxicity is thought to play key roles in brain neurodegeneration and stroke. Here we show that neuroprotection against excitotoxicity by trophic factors EFNB1 and brain-derived neurotrophic factor (called here factors) requires de novo formation of 'survival complexes' which are factor-stimulated complexes of N-methyl-d-aspartate receptor with factor receptor and presenilin 1. Absence of presenilin 1 reduces the formation of survival complexes and abolishes neuroprotection. EPH receptor B2- and N-methyl-d-aspartate receptor-derived peptides designed to disrupt formation of survival complexes also decrease the factor-stimulated neuroprotection. Strikingly, factor-dependent neuroprotection and levels of the de novo factor-stimulated survival complexes decrease dramatically in neurons expressing presenilin 1 familial Alzheimer disease mutants. Mouse neurons and brains expressing presenilin 1 familial Alzheimer disease mutants contain increased amounts of constitutive presenilin 1-N-methyl-d-aspartate recepy form downstream of neuronal damage. These findings have implications for the pathogenic effects of familial Alzheimer disease mutants and therapeutic strategies.Accumulation of assembled tau protein in the central nervous system is characteristic of Alzheimer's disease and several other neurodegenerative diseases, called tauopathies. Recent studies have revealed that propagation of assembled tau is key to understanding the pathological mechanisms of these diseases. Mouse models of tau propagation are established by injecting human-derived tau seeds intracerebrally; nevertheless, these have a limitation in terms of regulation of availability. To date, no study has shown that synthetic assembled tau induce tau propagation in non-transg