Proteotoxicity

About: Proteotoxicity is a research topic. Over the lifetime, 549 publications have been published within this topic receiving 23151 citations.

Chaperone-mediated autophagy: dedicated saviour and unfortunate victim in the neurodegeneration arena

Abstract: The importance of cellular quality-control systems in the maintenance of neuronal homoeostasis and in the defence against neurodegeneration is well recognized. Chaperones and proteolytic systems, the main components of these cellular surveillance mechanisms, are key in the fight against the proteotoxicity that is often associated with severe neurodegenerative diseases. However, in recent years, a new theme has emerged which suggests that components of protein quality-control pathways are often targets of the toxic effects of pathogenic proteins and that their failure to function properly contributes to pathogenesis and disease progression. In the present mini-review, we describe this dual role as 'saviour' and 'victim' in the context of neurodegeneration for chaperone-mediated autophagy, a cellular pathway involved in the selective degradation of cytosolic proteins in lysosomes.

Chaperone-mediated autophagy: a gatekeeper of neuronal proteostasis.

Abstract: Different types of autophagy co-exist in all mammalian cells, however, the specific contribution of each of these autophagic pathways to the maintenance of cellular proteostasis and cellular function remains unknown. In this work, we have investigated the consequences of failure of chaperone-mediated autophagy (CMA) in neurons and compared the impact, on the neuronal proteome, of CMA loss to that of macroautophagy loss. We found that these autophagic pathways are non-redundant and that CMA is the main one responsible for maintenance of the metastable proteome (the one at risk of aggregation). We demonstrate that loss of CMA, as the one that occurs in aging, has a synergistic effect with the proteotoxicity associated with neurodegenerative conditions such as Alzheimer disease (AD) and, conversely, that, pharmacological enhancement of CMA is effective in improving both behavior and pathology in two different AD mouse models.

In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders.

Abstract: The heat shock response (HSR) is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders.

The receptor for advanced glycation endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and exploiting common ground for novel amyloidosis therapies.

Abstract: Proteotoxicity plays a key role in many devastating human disorders, including Alzheimer's, Huntington's and Parkinson's diseases; type 2 diabetes; systemic amyloidosis; and cardiac dysfunction, to name a few. The cellular mechanisms of proteotoxicity in these disorders have been the focus of considerable research, but their role in prevalent and morbid disorders, such as diabetes, is less appreciated. There is a large body of literature on the impact of glucotoxicity and lipotoxicity on insulin-producing pancreatic β-cells, and there is increasing recognition that proteotoxicty plays a key role. Pancreatic islet amyloidosis by the hormone IAPP, the production of advanced glycation endproducts (AGE), and insulin misprocessing into cytotoxic aggregates are all sources of β-cell proteotoxicity in diabetes. AGE, produced by the reaction of reducing sugars with proteins and lipids are ligands for the receptor for AGE (RAGE), as are the toxic pre-fibrillar aggregates of IAPP produced during amyloid formation. The mechanisms of amyloid formation by IAPP in vivo or in vitro are not well understood, and the cellular mechanisms of IAPP-induced β-cell death are not fully defined. Here, we review recent findings that illuminate the factors and mechanisms involved in β-cell proteotoxicity in diabetes. Together, these new insights have far-reaching implications for the establishment of unifying mechanisms by which pathological amyloidoses imbue their injurious effects in vivo.