Modern Pathology: Protein Mis-Folding and Mis-Processing in Complex Disease

Introduction In order to develop a model for investigating the genes that contribute to retinal degeneration, we examined the early graded photochemical stress response in the adult zebrafish (Danio rerio) retina and investigated the role of an NMDA inhibitor, thiokynurenate. Methods Following intravitreal injection of rose bengal (6 or 12 mg/mL), light (37×103 or 83×103 lx) was directed onto the central retina with and without 400 nM thiokynurenate. Histologic and electron microscopic analysis was performed at 2 and 4 h and gene expression analysis was carried out at 2, 4 and 6 h. Results Light and electron microscopy demonstrated a graded photochemical response in photoreceptor, nuclear, and ganglion cell layer thickness. Increased vacuolation of the inner plexiform layer was also observed. The inhibitor produced a distinct lesion pattern. Cellular stress genes were elevated in low and high lesions, while some homeobox gene expression was reduced with thiokynurenate. Discussion The phenotypic and genetic changes observed from this model can serve as a basis for understanding the pathology of retinal oxidative and cellular stress. These changes may aid our understanding of aging and macular degeneration.

show abstract

“…5A). This may signify membrane alteration, cellular dysfunction and ultimate photoreceptor degeneration (Fadiel et al, 2007). …”

Section: Discussionmentioning

confidence: 99%

A zebrafish retinal graded photochemical stress model

Eichenbaum

Cinaroglu

Eichenbaum

et al. 2009

Journal of Pharmacological and Toxicological Methods

View full text Add to dashboard Cite

show abstract

“…On the verge of comprehension of the origin of internal rotational barriers, it is essential to understand molecular conformational changes, which are at the heart of fundamental topics in chemistry and biology such as protein folding/misfolding, signal transduction cascades in cells, and chemical reactivity for individual molecules (regio-, diastereo-, and enantioselectivity). Nevertheless, there still exists great controversy over the origin of the internal rotational barrier even for as simple a molecule as ethane .…”

Section: Introductionmentioning

confidence: 99%

Fisher Information and Steric Effect: Study of the Internal Rotation Barrier of Ethane

Esquivel

Liu

Angulo³

et al. 2011

J. Phys. Chem. A

View full text Add to dashboard Cite

On the basis of a density-based quantification of the steric effect [Liu, S. B. J. Chem. Phys.2007, 126, 244103], the origin of the internal rotation barrier between the eclipsed and staggered conformers of ethane is systematically investigated in this work from an information-theoretical point of view by using the Fisher information measure in conjugated spaces. Two kinds of computational approaches are considered in this work: adiabatic (with optimal structure) and vertical (with fixed geometry). The analyses are performed systematically by following, in each case, the conformeric path by changing the dihedral angle from 0 to 180° . This is calculated at the HF, MP2, B3LYP, and CCSD(T) levels of theory and with several basis sets. Selected descriptors of the densities are utilized to support the observations. Our results show that in the adiabatic case the eclipsed conformer possesses a larger steric repulsion than the staggered conformer, but in the vertical cases the staggered conformer retains a larger steric repulsion. Our results verify the plausibility for defining and computing the steric effect in the post-Hartree-Fock level of theory according to the scheme proposed by Liu.

show abstract

“…Therefore, membrane protein folding can be re-routed in the pathophysiological direction by both mutations and changes in protein environment including the membrane lipid composition. Errors in insertion (Milenkovic et al, 2007), folding (Lin and Liu, 2006), localization and intracellular trafficking (Aridor and Hannan, 2000), processing (Fadiel et al, 2007) or degradation (Gelman and Kopito, 2003), and turnover (Sambamurti et al, 2006) of integral transmembrane proteins are responsible for numerous diseases including neurodegenerative cerebral amyloidoses, cystic fibrosis and others (Harrison et al, 2007). Misfolded proteins fail to be degraded and become prone to formation of toxic aggregates.…”

Section: Alzheimer's and Scapies Diseases-mentioning

confidence: 99%

Lipids in the Assembly of Membrane Proteins and Organization of Protein Supercomplexes: Implications for Lipid-linked Disorders

Bogdanov¹,

Mileykovskaya²,

Dowhan

2008

Subcellular Biochemistry

127

View full text Add to dashboard Cite

Lipids play important roles in cellular dysfunction leading to disease. Although a major role for phospholipids is in defining the membrane permeability barrier, phospholipids play a central role in a diverse range of cellular processes and therefore are important factors in cellular dysfunction and disease. This review is focused on the role of phospholipids in normal assembly and organization of the membrane proteins, multimeric protein complexes, and higher order supercomplexes. Since lipids have no catalytic activity, it is difficult to determine their function at the molecular level. Lipid function has generally been defined by affects on protein function or cellular processes. Molecular details derived from genetic, biochemical, and structural approaches are presented for involvement of phosphatidylethanolamine and cardiolipin in protein organization. Experimental evidence is presented that changes in phosphatidylethanolamine levels results in misfolding and topological misorientation of membrane proteins leading to dysfunctional proteins. Examples are presented for diseases in which proper protein folding or topological organization is not attained due to either demonstrated or proposed involvement of a lipid. Similar changes in cardiolipin levels affects the structure and function of individual components of the mitochondrial electron transport chain and their organization into supercomplexes resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction has been linked to reduced cardiolipin levels are described. Therefore, understanding the principles governing lipid-dependent assembly and organization of membrane proteins and protein complexes will be useful in developing novel therapeutic approaches for disorders in which lipids play an important role.

show abstract

Modern Pathology: Protein Mis-Folding and Mis-Processing in Complex Disease

Cited by 11 publications

References 77 publications

A zebrafish retinal graded photochemical stress model

A zebrafish retinal graded photochemical stress model

Fisher Information and Steric Effect: Study of the Internal Rotation Barrier of Ethane

Lipids in the Assembly of Membrane Proteins and Organization of Protein Supercomplexes: Implications for Lipid-linked Disorders

Contact Info

Product

Resources

About