Successful therapies for Alzheimerâ€™s disease: why so many in animal models and none in humans?

Franco, Rafael; Cedazo-Minguez, Ángel

doi:10.3389/fphar.2014.00146

Cited by 151 publications

(120 citation statements)

References 114 publications

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“…Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 .…”

mentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

140

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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mentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

140

126

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“…104 Early on, the discovery that neurodegenerative diseases such as AD were invariably accompanied by the accumulation of amyloid aggregates or plaques prompted the conclusion that the aggregates themselves were toxic but, as murine models of the disease were developed in the recent past, a more nuanced view has emerged. 105 As noted above, amyloidosis in the cardiac system is well-characterized, with multiple proteins such as transthyretin, the immunoglobulin light and heavy chains, serum amyloid A, atrial natriuretic factor and a subset of the apolipoproteins confirmed as being amyloidogenic in the heart. 106 However, the study of other cardiac diseases that are characterized by the intracellular deposition of proteinaceous aggregates has been instructive as well in determining the pathogenic sequelae associated with abnormal peptide aggregates in the cardiomyocyte.…”

Section: Mechanistic Basis For Protein Aggregation Toxicitymentioning

confidence: 96%

Proteotoxicity and Cardiac Dysfunction

2013

N Engl J Med

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Baseline physiological function of the mammalian heart is under the constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally and this depends upon them assuming and maintaining proper conformation. This review explores the multiple defenses a cell may employ for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in the face of normal or pathologic stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In the absence of these corrective processes, they may become toxic to the cell. Herein, we explore some of the underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes as these misfolded proteins can lead to aggregation or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of the cell's ability to maintain protein homeostasis. Some underlying mechanisms are discussed and the therapeutic potential of interfering with proteotoxicity in the heart is explored.

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“…5 The goal of such a model is to replicate the salient disease features at the expense of the extraneous ones. For example, modeling flight would entail defying gravity, but without the need for building a machine with beaks or feathers.…”

Section: Why So Many Drugs Have Failedmentioning

confidence: 99%