Alice Goode

Bio: Alice Goode is an academic researcher from University of Nottingham. The author has contributed to research in topics: Sequestosome-1 Protein & Membrane. The author has an hindex of 9, co-authored 12 publications receiving 398 citations.

Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD.

Abstract: Growing evidence implicates impairment of autophagy as a candidate pathogenic mechanism in the spectrum of neurodegenerative disorders which includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS-FTLD). SQSTM1, which encodes the autophagy receptor SQSTM1/p62, is genetically associated with ALS-FTLD, although to date autophagy-relevant functional defects in disease-associated variants have not been described. A key protein-protein interaction in autophagy is the recognition of a lipid-anchored form of LC3 (LC3-II) within the phagophore membrane by SQSTM1, mediated through its LC3-interacting region (LIR), and notably some ALS-FTLD mutations map to this region. Here we show that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B. We place our observations on a firm quantitative footing by showing the L341V-mutant LIR is associated with a ∼3-fold reduction in LC3B binding affinity and using protein NMR we rationalize the structural basis for the effect. This functional deficit is realized in motor neuron-like cells, with the L341V mutant EGFP-mCherry-SQSTM1 less readily incorporated into acidic autophagic vesicles than the wild type. Our data supports a model in which the L341V mutation limits the critical step of SQSTM1 recruitment to the phagophore. The oligomeric nature of SQSTM1, which presents multiple LIRs to template growth of the phagophore, potentially gives rise to avidity effects which amplify the relatively modest impact of any single mutation on LC3B binding. Over the lifetime of a neuron, impaired autophagy could expose a vulnerability, which ultimately tips the balance from cell survival toward cell death.

Recent advances in understanding the molecular basis of Paget disease of bone

Abstract: Paget disease of bone (PDB) is a relatively common disorder characterised by increased bone turnover within discrete lesions throughout the skeleton. The condition has a strong genetic component, with mutations affecting the SQSTM1 gene that encodes the p62 protein often found in PDB patients, although environmental factors also play an important role in disease aetiology. The precise disease mechanism(s) in familial forms and sporadic forms of PDB is unclear, although defective RANK-NF-κB signalling has been suggested to contribute to the increased activity of pagetic osteoclasts in the former. Here, there is a review of recent advances in the understanding of the molecular basis of PDB with particular emphasis on findings since 2008, and focus on newly defined functions of the p62 protein upon which SQSTM1 mutations may impact in the development of the pagetic phenotype.

A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease.

Abstract: Mutations in the SQSTM1 gene were identified as a common cause of Paget's disease of bone (PDB) but experimental evidence demonstrated that SQSTM1 mutation is not sufficient to induce PDB in vivo Here, we identified two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the TNFRSF11A gene, associated with PDB and with the severity of phenotype in a large population of 654 unrelated patients that were previously screened for SQSTM1 gene mutations The largest effect was found for the T575C variant, yielding an odds ratio of 129 (p = 0003), with the C allele as the risk allele Moreover, an even more significant p-value (p = 00002) was observed in the subgroup of patients with SQSTM1 mutation, with an odds ratio of 171 Interestingly, patients with the C allele also showed an increased prevalence of polyostotic disease (68%, 53%, and 51% in patients with CC, CT, and TT genotypes, respectively; p = 001), as well as an increased number of affected skeletal sites (29, 25, and 20 in patients with CC, CT, and TT genotypes, respectively, p = 0008) These differences increased when analyses were restricted to cases with SQSTM1 mutation In human cell lines, cotrasfection with mutated SQSTM1 and TNFRSF11AA192 produced a level of activation of NFκB signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11AV192, confirming genetics and clinical evidences These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations © 2012 American Society for Bone and Mineral Research

Proteasomal and Autophagic Degradation Systems.

Abstract: Autophagy and the ubiquitin-proteasome system are the two major quality control pathways responsible for cellular homeostasis. As such, they provide protection against age-associated changes and a plethora of human diseases. Ubiquitination is utilized as a degradation signal by both systems, albeit in different ways, to mark cargoes for proteasomal and lysosomal degradation. Both systems intersect and communicate at multiple points to coordinate their actions in proteostasis and organelle homeostasis. This review summarizes molecular details of how proteasome and autophagy pathways are functionally interconnected in cells and indicates common principles and nodes of communication that can be therapeutically exploited.

p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation.

Abstract: The ubiquitin–proteasome system (UPS) and autophagy are two distinct and interacting proteolytic systems. They play critical roles in cell survival under normal conditions and during stress. An increasing body of evidence indicates that ubiquitinated cargoes are important markers of degradation. p62, a classical receptor of autophagy, is a multifunctional protein located throughout the cell and involved in many signal transduction pathways, including the Keap1–Nrf2 pathway. It is involved in the proteasomal degradation of ubiquitinated proteins. When the cellular p62 level is manipulated, the quantity and location pattern of ubiquitinated proteins change with a considerable impact on cell survival. Altered p62 levels can even lead to some diseases. The proteotoxic stress imposed by proteasome inhibition can activate autophagy through p62 phosphorylation. A deficiency in autophagy may compromise the ubiquitin–proteasome system, since overabundant p62 delays delivery of the proteasomal substrate to the proteasome despite proteasomal catalytic activity being unchanged. In addition, p62 and the proteasome can modulate the activity of HDAC6 deacetylase, thus influencing the autophagic degradation.