Structure and nanostructure in ionic liquids.

Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities

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.

Proteasomal and Autophagic Degradation Systems.

Amyotrophic lateral sclerosis

Reversible deactivation radical polymerization (RDRP) has revolutionized modern polymer chemistry over the past two decades, thus laying the groundwork for the synthesis of complex macromolecules and enabling the preparation of previously inaccessible materials. Reversible addition-fragmentation chain transfer (RAFT) polymerization has emerged as one of the most promising techniques because of its functional group tolerance, applicability to a wide range of vinyl monomers, and its nondemanding experimental conditions. However, despite the promise and clearly demonstrated utility of RAFT, limitations of the method sometimes still exist, including the occasional need for extended polymerization times, limited access to high molecular weight polymers, low “livingness” due to unavoidable radical termination events, etc. This Perspective focuses on recent advances that have been specifically designed to address many of these perceived limitations to reinforce the promise of RAFT for the synthesis of complex an...

Expanding the Scope of RAFT Polymerization: Recent Advances and New Horizons

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.

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2016.1170257

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

Rotating frame nuclear Overhauser effect spectroscopy (ROESY) has been used to probe the chemical environment in dialkyl-imidazolium ionic liquids. A qualitative use of the distance dependence of the rotating frame Overhauser enhancement (ROE) has shown that reactants and intermediates have variable affinities for the distinct domains that are proposed within ionic liquids. A model system based on the free radical polymerisation of methyl methacrylate (MMA) has been developed to investigate any differing affinities, and to investigate the hypothesis that segregation of species between domains within the ionic liquid structure is contributory towards the generation of unexpectedly high rates of polymerisation and final polymer molecular weights.

NMR as a probe of nanostructured domains in ionic liquids: Does domain segregation explain increased performance of free radical polymerisation?

The influence of domain segregation in ionic liquids upon controlled polymerisation mechanisms: RAFT polymerisation

The conversion of readily available monosaccharides to high-value amino alcohols using a key biocatalytic step is an attractive strategy for the preparation of these chiral synthons. Here, we report a previously undescribed example of the direct amination of monosaccharides, which exist predominantly in their cyclic form at equilibrium, using amine transaminase biocatalysts, providing access to a panel of amino alcohols in moderate to high conversion and isolated yield. A recently developed high-throughput colorimetric screen, employing o-xylylenediamine, was initially used to identify amine transaminase enzymes displaying this activity towards cyclic sugars and reactions were successfully scaled-up using isopropylamine.

/pdf/conversion-of-aldoses-to-valuable-o-amino-alcohols-using-3e0aj2su1a.pdf

Kevin Butler

Papers

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

NMR as a probe of nanostructured domains in ionic liquids: Does domain segregation explain increased performance of free radical polymerisation?

The influence of domain segregation in ionic liquids upon controlled polymerisation mechanisms: RAFT polymerisation

Conversion of Aldoses to Valuable ω-Amino Alcohols Using Amine Transaminase Biocatalysts