title: Neurodegenerative disorders: dysregulation of a carefully maintained balance?
abstract: The aggregation of misfolded proteins has long been regarded as a pathological event in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the exact molecular mechanisms that govern protein metabolism that may lead to toxicity remain largely unclear. Originally targeted as the causative agent, it has since become evident that aggregation formation may not be necessary for disease progression and studies show that they may even serve functional and protective roles. Although the focus has since shifted to the toxicity of intermediate protein species preceding aggregation formation, many questions remain: Is the blame for the neural destruction to be put on one event alone, or rather on a state of cellular disequilibrium resulting from multiple events? If the cause is multifactorial, then what triggers the toxic cascade and how can this be targeted therapeutically? In order to understand the origin of toxicity, the exact underlying mechanism and impact of each contributing process must be assessed. Therefore, the structural properties, mechanism of formation, cytotoxic and/or protective effects, as well as the clinical impact of protein intermediates and aggregates will be reviewed here with the goal to establish a neurodegenerative disease model aimed at improving current therapeutics, which may ultimately contribute towards improved treatment modalities.
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: chrisna@sun.ac.za.
authors.forename: Chrisna
authors.initials: C
authors.lastname: Swart
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: William
authors.initials: W
authors.lastname: Haylett
authors.affiliation: South African Medical Research Council Centre for Tuberculosis Research, Cape Town, South Africa.
authors.forename: Craig
authors.initials: C
authors.lastname: Kinnear
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Glynis
authors.initials: G
authors.lastname: Johnson
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Soraya
authors.initials: S
authors.lastname: Bardien
authors.affiliation: Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Cape Town, South Africa. Electronic address: bloos@sun.ac.za.
authors.forename: Ben
authors.initials: B
authors.lastname: Loos
mesh_terms: D000818:Animals; D006706:Homeostasis; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D057165:Proteostasis Deficiencies / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D009419:Nerve Tissue Proteins; D066329:Protein Aggregates
keywords: Aggregation; Cytotoxic; Disequilibrium; Homeostasis; Neurodegeneration