Special Issue "Protein Aggregation"

Guest Editor
Prof. Dr. Ludmilla A. Morozova-Roche
Department of Medical Biochemistry and Biophysics, Umeå Univeristy, Umeå, SE 90781, Sweden
Website: http://www.medchem.umu.se/english/research/principal-investigators/morozova-roche/
E-Mail: ludmilla.morozova-roche@medchem.umu.se
Phone: +46907865283
Fax: +46 90 786 9795

Dear Colleagues,

Protein aggregation is the most common and problematic manifestation of protein instability encountered during all stages of protein purification and applications. The formation of unstructured aggregates effectively reduces the quantity of functional compounds in solutions. If protein aggregates are not eliminated by clearance mechanisms from the body, the accumulation of protein deposits is associated with growing number of protein conformational diseases. Among proteins aggregates the structured aggregation involving the formation of cross-beta-sheet containing amyloid fibrils and oligomers received particular attention being a leading course of age-related degenerative amyloid diseases. Evidence accumulated that in some cases the regulated protein aggregation can fulfill useful functions of polypeptide storage or sequestration and minimization of diffusion of highly reactive and toxic species. As a result the protein aggregation became the central theme of much current research aimed at understanding the mechanisms underlying this process and measures increasing proteins stability and reducing the propensity of the spontaneous and often undesirable aggregation. Here we present the collection of articles presenting the broad overview of the state of this rapidly developing field and the challenges met by using current knowledge of the mechanisms of protein molecular assemblies and stability.

Prof. Dr. Ludmilla A. Morozova-Roche
Guest Editor

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• protein aggregation
• amyloid formation
• self-assembly
• stability
• conformational plasticity
• nucleation
• inhibition

Title: Protein Aggregation in Amyotrophic Lateral Sclerosis
Authors: Nathalie Wilmans, Elke Bogaert and Ludo Van Den Bosch
Affiliation: Laboratory of Neurobiology, Vesalius Research Center, VIB, University of Leuven, Belgium; E-Mail: Nathalie.Wilmans@med.kuleuven.be
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by the selective loss of motor neurons in the motor cortex, brain stem and spinal cord. This neuronal loss results in muscle atrophy, paralysis and the death of the patient on average 3-5 years after diagnosis. Despite many years of research the cause of this disease is still unknown. Several mechanisms have been suggested to play a role in the pathogenesis of ALS and one of these mechanisms is protein aggregation. The recent identification of causative mutations in the TDP-43 and FUS genes and the presence of the respective mutant proteins in aggregates in ALS patients carrying these mutations emphasize a possible role for protein aggregation in the pathogenesis of ALS. Interestingly, protein aggregation is also detected in patients lacking mutations in the currently known ALS genes, indicating a possible common mechanism for all ALS patients. This review provides an overview of the different genes mutated in ALS and the presence of their mutant protein products in aggregates, as revealed by research on post mortem ALS patient material and diverse in vitro and in vivo models of ALS.

Type of Paper: Review
Title: Protein Misfolding and Aggregation as a Common Molecular Pathogenesis of Neurodegenerative Diseases
Author: Yoshitaka Nagai ^{1, 2}
Affiliation: ¹ Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan; E-Mail: nagai@ncnp.go.jp
² Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan
Abstract: Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and the polyglutamine (polyQ) diseases, have been defined as a group of intractable disorders with unknown etiology, which are characterized by the progressive degeneration of neurons in various regions of the brain, resulting in neurological and psychiatric symptoms. However, molecular genetics and biological studies have revealed that most neurodegenerative diseases are caused by protein misfolding and aggregation, and hence they are thought to belong to the so-called protein misfolding diseases. Moreover, recent emerging evidence has suggested that these misfolded protein aggregates have intrinsic characteristics to be propagated through prion-like infectious mechanisms. Therefore, various therapeutic strategies targeting protein misfolding and aggregation are being extensively explored. In this review, focusing on the polyQ diseases, I will introduce how protein misfolding and aggregation contribute to the pathogenesis of neurodegenerative diseases, and their therapeutic approaches using molecular chaperones, peptides, and small chemical compounds. Anti-misfolding and -aggregation agents which are commonly effective for a diverse range of neurodegenerative diseases are eagerly expected be developed in the near future.

Type of Paper: Review
Title: The Slowly Aggregating Salmon Calcitonin: a Useful Tool in the Study of the Amyloid Oligomers Structure and Activity
Authors: Marco Diociaiuti ¹, Maria Cristina Gaudiano ² and Fiorella Malchiodi-Albedi ³
Affiliations: ¹ Department of Technology and Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Roma, Italy; E-Mail: marco.diociaiuti@iss.it
² Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Roma, Italy; E-Mail: mariacristina.gaudiano@iss.it
³ Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Roma, Italy; E-Mail: fiorella.malchiodi@iss.it
Abstract: Amyloid proteins of different chemical nature share the tendency to misfold and aggregate in a similar way, following common aggregation steps. The process includes the formation of dimers, trimers, low molecular weight prefibrillar oligomers, characterized by the typical morphology of globules less than 10 nm diameter. The globules spontaneously form linear or annular structures and, eventually, mature fibers. The rate of this process depends on characteristics intrinsic to the different proteins and to environmental conditions. In the case of neurodegenerative diseases, it is now generally agreed that the pathogenic aggregates are not the mature fibrils, but the intermediate, soluble oligomers. However, the molecular mechanism by which these oligomers trigger neuronal damage is still unclear. In particular, it is not clear if there is a peculiar structure at the basis of the neurotoxic effect and how this structure interacts with neurons. This review will focus on the results we obtained using salmon Calcitonin, an amyloid protein characterized by a very slow aggregation rate, which allowed us to closely monitor the aggregation process. We used it as a tool to investigate the characteristics of amyloid oligomers formation and their interactions with neuronal cells. Our results seem to indicate that small globules of about 6 nm could be the responsible for the neurotoxic effects. Moreover, our data suggest that the rich content in lipid rafts of neuronal cell plasma membrane may render neurons particularly vulnerable to the amyloid protein toxic effect.
Keywords: Amyloid Oligomers; Aggregation; Lipid Rafts

Type of Paper: Review
Title: Unraveling the Early Events of Aβ Aggregation: Techniques for the Determination of Aβ Aggregate Size and Quantity
Authors: N. Elizabeth Pryor ¹, Christa N. Hestekin ¹ and Melissa A. Moss ²
Affiliations: ¹Ralph E. Martin Department of Chemical Engineering, 3202 Bell Engineering Center, 1 University of Arkansas, Fayetteville, AR 72701, USA; E-Mail: npryor@uark.edu (N.E.P.); chesteki@uark.edu (C.N.H.)
² 3C15 Swearingen Chemical Engineering, University of South Carolina, 301 Main Street, Columbia, SC 29208, USA; E-Mail: MOSSME@cec.sc.edu (M.A.M.)
Abstract: The aggregation of proteins into insoluble amyloid fibrils is a devastating pathological process that contributes to the onset of numerous diseases. An array of techniques is available to study the different stages of the amyloid aggregation process.  Recently, emphasis has been placed upon the analysis of oligomeric amyloid species, which have been hypothesized to play a key role in disease progression. This paper will review techniques utilized to study aggregation of the amyloid-b protein (Aβ) associated with Alzheimer’s disease. In particular, the review will focus on techniques that provide information about the size and/or quantity of oligomeric Ab species formed during the early stages of aggregation, including SDS-PAGE, Western blotting, capillary electrophoresis, mass spectrometry, and dye binding.