Mini-Symposium Chaperones in Neurodegeneration (original) (raw)
Iris Lindberg,1 James Shorter,2 R. Luke Wiseman,3 Fabrizio Chiti,4 Chad A. Dickey,5 and XPamela J. McLean6 1University of Maryland School of Medicine, Baltimore, Maryland 21201, 2University of Pennsylvania, Philadelphia, Pennsylvania 19104, 3The Scripps Research Institute, La Jolla, California 92037, 4University of Florence, 50121 Florence, Italy, 5University of South Florida, Tampa, Florida 33620, and 6Mayo Clinic, Jacksonville, Florida 32224
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Chaperone-dependent Neurodegeneration: A Molecular Perspective on Therapeutic Intervention
Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as "clients," have major roles in the pathogenesis of numerous neurological disorders, including tau in Alzheimer's disease, α-synuclein and LRRK2 in Parkinson's disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington's disease. Recent work has demonstrated that the use of chemical compounds which inhibit the activity of molecular chaperones subsequently alter the fate of aberrant clients. Inhibition of Hsp90 and Hsc70, two major molecular chaperones, has led to a greater understanding of how chaperone triage decisions are made and how perturbing the chaperone system can promote clearance of these pathogenic clients. Described here are major pathways and components of several prominent neurological dis...
Chaperones and aging: role in neurodegeneration and in other civilizational diseases
Neurochemistry International, 2002
Chaperones are highly conserved proteins responsible for the preservation and repair of the correct conformation of cellular macromolecules, such as proteins, RNAs, etc. Environmental stress leads to chaperone (heat-shock protein, stress protein) induction reflecting the protective role of chaperones as a key factor for cell survival and in repairing cellular damage after stress. The present review summarizes our current knowledge about the chaperone-deficiency in the aging process, as well as the possible involvement of chaperones in neurodegenerative diseases, such as in Alzheimer's, Parkinson's, Huntington-and prion-related diseases. We also summarize a recent theory implying chaperones as "buffers" of variations in the human genome, which role probably increased during the last 200 years of successful medical practice minimizing natural selection. Chaperone-buffered, silent mutations may be activated during the aging process, which leads to the phenotypic exposure of previously hidden features and might contribute to the onset of polygenic diseases, such as atherosclerosis, cancer, diabetes and several neurodegenerative diseases.
Alzheimer's Disease and Molecular Chaperones: Current Knowledge and the Future of Chaperonotherapy
Background: Alzheimer's disease (AD) is a dementia, a neurodegenerative condition , and a protein-misfolding disease or proteinopathy, characterized by protein deposits, extracellular plaques and intracellular neurofibrillary tangles, which contain the AD's typical pathological proteins, abnormal-amyloid and hyperphosphorylated tau, respectively, and are located predominantly in the cortex of the frontal, parietal, and temporal brain lobes. What is the role of molecular chaperones in AD? Data indicate that molecular chaperones, also known as Hsp, are involved in AD, probably displaying protective roles and/or acting as pathogenic factors as it occurs in chaperonopathies in which case AD would be suitable to chaperonotherapy. Hsp60, Hsp70, and Hsp90 can be augmented and overexpressed or diminished and downregulated in various situations in AD affected tissues and cells, indicating they are active during disease development and progression. Question: What is the role of molecular chaperones in AD? Data indicate that molecular chaperones, also known as Hsp, are involved in AD, probably displaying protective roles and/or acting as pathogenic factors as it occurs in chaperonopathies in which case AD would be suitable to chaperonotherapy. Objective: Investigate the role of Hsp in AD, focusing on Hsp60, Hsp70, and Hsp90. Method: Critical examination of published data. Results: Hsp60, Hsp70, and Hsp90 can be augmented and overexpressed or diminished and downregulated in various situations in AD affected tissues and cells, indicating they are active during disease development and progression. Conclusion and Perspectives: Notwithstanding that the roles and mechanisms of action of chaperones in AD are still incompletely understood, there is already enough evidence to encourage the development of therapeutic strategies targeting them, either to block their activity in case they promote disease progression or to boost their performance when they are protective. The latter is an example of positive chaperonotherapy, which also includes chaperone replacement via gene or protein administration. On the contrary, if a chaperone is found to help the disease, it has to be blocked or eliminated, which constitute modalities of negative chaperonotherapy.
Molecules, 2010
Human neurodegenerative diseases arise from a wide array of genetic and environmental factors. Despite the diversity in etiology, many of these diseases are considered "conformational" in nature, characterized by the accumulation of pathological, misfolded proteins. These misfolded proteins can induce cellular stress by overloading the proteolytic machinery, ultimately resulting in the accumulation and deposition of aggregated protein species that are cytotoxic. Misfolded proteins may also form aberrant, non-physiological protein-protein interactions leading to the sequestration of other normal proteins essential for cellular functions. The progression of such disease may therefore be viewed as a failure of normal protein homeostasis, a process that involves a network of molecules regulating the synthesis, folding, translocation and clearance of proteins. Molecular chaperones are highly conserved proteins involved in the folding of nascent proteins, and the repair of proteins that have lost their typical conformations. These functions have therefore made molecular chaperones an active area of investigation within the field of conformational diseases. This review will discuss the role of molecular chaperones in neurodegenerative diseases, highlighting their functional classification, regulation, and therapeutic potential for such diseases. OPEN ACCESS Molecules 2010, 15 6860
Modulation of neurodegeneration by molecular chaperones
Nature Reviews Neuroscience, 2005
Many systemic and neurodegenerative disorders, termed 'protein-misfolding disorders' , or perhaps more appropriately 'protein-conformational disorders' , are characterized by the accumulation of intracellular or extracellular PROTEIN AGGREGATES. Post-mitotic cells, such as neurons, are particularly vulnerable to the detrimental effects of misfolded and/or aggregated proteins because they cannot dilute potentially toxic species through cell division. To make matters worse, misfolded proteins are thought to accumulate in neurons and in other cells as a result of normal ageing-concomitant with a decrease in proteasome activity and with alterations in the induction and/or functional capacity of MOLECULAR CHAPERONES 1. Collectively, these factors might account for the late onset of neurodegenerative diseases that are linked to protein aggregation 2. This review focuses on studies that have investigated the function of molecular chaperones in neurodegenerative disorders that are characterized by the accumulation of aggregated protein, including Alzheimer's disease (AD), Parkinson's disease (PD), familial amyotrophic lateral sclerosis (FALS), Huntington's disease (HD) and related polyglutamine (polyQ) expansion diseases. Recent evidence indicates that chaperones are potent suppressors of neurodegeneration and are, therefore, promising therapeutic targets for protein conformational disorders. Protein aggregation and molecular chaperones Although the amino acid sequence of a protein contains all the information that is required to dictate proper folding into a functional, three-dimensional structure 3 , the crowded intracellular milieu places constraints on the folding of polypeptides, thereby promoting misfolding and aggregation. As a consequence, protein folding in vivo is typically not spontaneous 4 , and organisms from archaea to eukaryotes have evolved a highly conserved class of proteins called molecular chaperones that prevent inappropriate interactions within and between non-native polypeptides, enhance the efficiency of de novo protein folding and promote the refolding of proteins that have become misfolded as a result of cellular stress 5. Importantly, chaperones only
Chaperone signalling complexes in Alzheimer's disease
Journal of Cellular and Molecular Medicine, 2009
Molecular chaperones and heat shock proteins (Hsp) have emerged as critical regulators of proteins associated with neurodegenerative disease pathologies. The very nature of the chaperone system, which is to maintain protein quality control, means that most nascent proteins come in contact with chaperone proteins. Thus, amyloid precursor protein (APP), members of the gamma-secretase complex (presenilin 1 [PS1] collectively), the microtubule-associated protein tau (MAPT) as well as a number of neuroinflammatory components are all in contact with chaperones from the moment of their production. Chaperones are often grouped together as one machine presenting abnormal or mutant proteins to the proteasome for degradation, but this is not at all the case. In fact, the chaperone family consists of more than 100 proteins in mammalian cells, and the primary role for most of these proteins is to protect clients following synthesis and during stress; only as a last resort do they facilitate protein degradation. To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds. Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation. In the case of Alzheimer's disease (AD), a number of studies have recently emerged describing the impact that these chaperones have on the proteotoxic effects of tau and amyloid- accumulation. Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.
Applied Sciences
The chaperone (or chaperoning) system (CS) constitutes molecular chaperones, co-chaperones, and chaperone co-factors, interactors and receptors, and its canonical role is protein quality control. A malfunction of the CS may cause diseases, known as the chaperonopathies. These are caused by qualitatively and/or quantitatively abnormal molecular chaperones. Since the CS is ubiquitous, chaperonopathies are systemic, affecting various tissues and organs, playing an etiologic-pathogenic role in diverse conditions. In this review, we focus on chaperonopathies involved in the pathogenic mechanisms of diseases of the central and peripheral nervous systems: the neurochaperonopathies (NCPs). Genetic NCPs are linked to pathogenic variants of chaperone genes encoding, for example, the small Hsp, Hsp10, Hsp40, Hsp60, and CCT-BBS (chaperonin-containing TCP-1- Bardet–Biedl syndrome) chaperones. Instead, the acquired NCPs are associated with malfunctional chaperones, such as Hsp70, Hsp90, and VCP/p...
International Journal of Molecular Sciences
Many neurodegenerative disorders are characterized by the abnormal aggregation of misfolded proteins that form amyloid deposits which possess prion-like behavior such as self-replication, intercellular transmission, and consequent induction of native forms of the same protein in surrounding cells. The distribution of the accumulated proteins and their correlated toxicity seem to be involved in the progression of nervous system degeneration. Molecular chaperones are known to maintain proteostasis, contribute to protein refolding to protect their function, and eliminate fatally misfolded proteins, prohibiting harmful effects. However, chaperone network efficiency declines during aging, prompting the onset and the development of neurological disorders. Extracellular vesicles (EVs) are tiny membranous structures produced by a wide range of cells under physiological and pathological conditions, suggesting their significant role in fundamental processes particularly in cellular communicat...
Behavioral Defects in Chaperone-Deficient Alzheimer's Disease Model Mice
PloS one, 2011
Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation. Neurotoxicity of amyloid-beta (Ab) aggregates and their deposition in senile plaques are hallmarks of Alzheimer's disease (AD). We observed that the overall content of aB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner. We hypothesized that aB-crystallin protects cells against Ab toxicity. To test this, we crossed aBcrystallin/HspB2 deficient (CRYAB-/-HSPB2-/-) mice with AD model transgenic mice expressing mutant human amyloid precursor protein. Transgenic and non-transgenic mice in chaperone-sufficient or deficient backgrounds were examined for representative behavioral paradigms for locomotion and memory network functions: (i) spatial orientation and locomotion was monitored by open field test; (ii) sequential organization and associative learning was monitored by fear conditioning; and (iii) evoked behavioral response was tested by hot plate method. Interestingly, aB-crystallin/HspB2 deficient transgenic mice were severely impaired in locomotion compared to each genetic model separately. Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases.