Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

Abstract

Alzheimer’s Disease (AD) is a progressive multifactorial age-related neurodegenerative disorder that causes the majority of deaths due to dementia in the elderly. Although various risk factors have been found to be associated with AD progression, the cause of the disease is still unresolved. The loss of proteostasis is one of the major causes of AD: it is evident by aggregation of misfolded proteins, lipid homeostasis disruption, accumulation of autophagic vesicles, and oxidative damage during the disease progression. Different models have been developed to study AD, one of which is a yeast model. Yeasts are simple unicellular eukaryotic cells that have provided great insights into human cell biology. Various yeast models, including unmodified and genetically modified yeasts, have been established for studying AD and have provided significant amount of information on AD pathology and potential interventions. The conservation of various human biological processes, including signal transduction, energy metabolism, protein homeostasis, stress responses, oxidative phosphorylation, vesicle trafficking, apoptosis, endocytosis, and ageing, renders yeast a fascinating, powerful model for AD. In addition, the easy manipulation of the yeast genome and availability of methods to evaluate yeast cells rapidly in high throughput technological platforms strengthen the rationale of using yeast as a model. This review focuses on the description of the proteostasis network in yeast and its comparison with the human proteostasis network. It further elaborates on the AD-associated proteostasis failure and applications of the yeast proteostasis network to understand AD pathology and its potential to guide interventions against AD.

The biological pathways of Alzheimer disease: a review

“…Interestingly, Tau accumulation can trigger a cycle where the presence of Tau inhibits ERAD (by binding HRD1): in turn ERAD inhibition leads to an increased Tau aggregation (together with other misfolded proteins) [186] . Misfolded protein continue accumulation ultimately lead to the activation of the Unfolded Protein Response, which trigger apoptosis and, consequently, neurodegeneration [320] , [321] . For a more in deep discussion on ERAD cascade please refer to [186] .…”

A Toxic Synergy between Aluminium and Amyloid Beta in Yeast

“…Saccharomyces cerevisiae has proven to be a facile model for studying AD, providing unprecedented insights into the underlying molecular basis of ageing and in deciphering the complexity of disease pathology involved in AD [ 13 , 15 , 16 ]. We have developed yeast-based models for investigating the effects of compounds that alleviate the toxicity associated with Aβ 42 and those that synergistically increase Aβ toxicity [ 17 , 18 , 19 ].…”

Trans-Chalcone Plus Baicalein Synergistically Reduce Intracellular Amyloid Beta (Aβ42) and Protect from Aβ42 Induced Oxidative Damage in Yeast Models of Alzheimer’s Disease

“…This phenomenon aligns well with human ageing and advocates that the yeast ageing can be an excellent tool to understand eukaryotic ageing [10]. Further elaboration on how yeast provides an excellent platform for studying AD is reviewed elsewhere [11][12][13]. In another study, differential gene expression analysis between GFP-Aβ 42 producing yeast compared with GFP producing yeast showed high expression of AHP1 in GFP-Aβ 42 producing cells [14].…”

“…Oxidative damage and aggregation of proteins are common manifestations of aging and are highly increased during AD [18,19]. Increasing evidence supports loss of proteostasis as the major pathological hallmark of AD, evident by accumulation of amyloid plaques and tau neurofibrillary tangles in the brain [12]. The toxicity of Aβ 42 peptide and ability to enhance intracellular ROS, damage mitochondria, cause stress and formation of amyloid plaques restricting brain function has been considered a major cause of AD [9,20,21].…”