Barry Shaw

TL;DR: It is shown that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B, a key protein-protein interaction in autophagy which could expose a vulnerability over the lifetime of a neuron, which ultimately tips the balance from cell survival toward cell death.

TL;DR: NMR relaxation dispersion experiments, coupled with concentration-dependent NMR, CD, isothermal titration calorimetry and fluorescence kinetic measurements, reveal that the p62 UBA domain forms a highly stable dimer, and the monomeric UBA appears to be the biologically active form and the dimer appears to been the inactive one.

TL;DR: Functional studies suggest that increased NF‐κB signaling, but not the impairment of ubiquitin binding, may be essential in the pathogenesis of PDB associated with SQSTM1 mutations.

TL;DR: The first characterization at the molecular, cellular, and functional level of a non‐UBA domain missense mutation (A381V) of SQSTM1 is presented, indicating that non‐ UBA and UBA domain mutations may exert their effects through a common mechanism involving dysregulated NF‐κB signaling.

TL;DR: The results suggest that SQ STM1 mutations within the KIR of SQSTM1/p62 contribute to aetiology of some cases of ALS-FTLD through a mechanism involving aberrant expression or regulation of oxidative response genes.