The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model

Abstract

Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, ALS. Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a 'co-factor derived membrane association model' wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association mediated toxic aggregation and survival time scale after ALS diagnosis.

Metabolic Engineering of Isoflavones: An Updated Overview

“…Cytochrome P450–mediated hydroxylation associated with 2,3-aryl migration of the B ring in 2S flavanones forms a 2-hydroxyisoflavanone using IFS ( Figure 4 ). Then, this is dehydrated into the isoflavones (genistein and daidzein) through the natural reaction catalyzed by specific dehydratase enzyme ( Kochs and Grisebach, 1986 ; Hakamatsuka et al, 1990 , 1998 ).…”

New Enantiomers of a Nor-Bisabolane Derivative and Two New Phthalides Produced by the Marine-Derived Fungus Penicillium chrysogenum LD-201810

“…In addition to the new compounds, two previously reported bisabolane sesquiterpenes 2 and 3, a phthalide derivative 6, and a chromone 7, were also isolated from this fungal strain. Based on detailed spectroscopic analysis as well as by comparisons with literature data, their structures were identified as hydroxysydonic acid (2) ( Hamasaki et al, 1978 ), sydowic acid (3) ( Hamasaki et al, 1975 ), rubralide C (6) ( Kimura et al, 2007 ), and 2,5-dimethyl-7-hydroxychromone (7) ( Kashiwada et al, 1984 ).…”

Perinatal Exposure of Bisphenol A Differently Affects Dendritic Spines of Male and Female Grown-Up Adult Hippocampal Neurons

“…Iguchi and coworkers demonstrated that BPA, injected into the mouse mother’s body (single s.c. injection), was transferred to the brains of fetus within 1 h via going through the immature blood-brain barrier ( Uchida et al, 2002 ). In contrast to the efficient detoxification of endocrine disrupters, such as BPA in the liver, detoxification in the brain may be less efficient due to the low level of drug-metabolizing enzymes in the brain ( Miksys and Tyndale, 2002 ; Miksys et al, 2002 ).…”

“…Upon perinatal exposure to BPA, BPA can penetrate much more easily into the brain of embryo and fetus where the blood-brain barrier is not completely developed ( Uchida et al, 2002 ). The detoxification of BPA in the brain is probably very weak due to the extremely low level of drug-metabolizing enzymes in the brain ( Miksys and Tyndale, 2002 ; Kishimoto et al, 2004 ; Chinta et al, 2005 ).…”