Quality control of the proteins associated with neurodegenerative diseases (original) (raw)
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Journal of Molecular Neuroscience, 2006
The formation of toxic protein aggregates is a common denominator to many neurodegenerative diseases and aging. Accumulation of toxic, possibly infectious protein aggregates induces a cascade of events, such as excessive inflammation, the production of reactive oxygen species, apoptosis and neuronal loss. A network of highly conserved molecular chaperones and of chaperone-related proteases controls the fold-quality of proteins in the cell. Most molecular chaperones can passively prevent protein aggregation by binding misfolding intermediates. Some molecular chaperones and chaperone-related proteases, such as the proteasome, can also hydrolyse ATP to forcefully convert stable harmful protein aggregates into harmless natively refoldable, or protease-degradable, polypeptides. Molecular chaperones and chaperone-related proteases thus control the delicate balance between natively folded functional proteins and aggregation-prone misfolded proteins, which may form during the lifetime and lead to cell death. Abundant data now point at the molecular chaperones and the proteases as major clearance mechanisms to remove toxic protein aggregates from cells, delaying the onset and the outcome of protein-misfolding diseases. Therapeutic approaches include treatments and drugs that can specifically induce and sustain a strong chaperone and protease activity in cells and tissues prone to toxic protein aggregations.
The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease
One of the shared hallmarks of neurodegenerative diseases is the accumulation of misfolded proteins. Therefore, it is suspected that normal proteostasis is crucial for neuronal survival in the brain and that the malfunction of this mechanism may be the underlying cause of neurodegenerative diseases. The accumulation of amyloid plaques (APs) composed of amyloid-beta peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed of misfolded Tau proteins are the defining pathological markers of Alzheimer’s disease (AD). The accumulation of these proteins indicates a faulty protein quality control in the AD brain. An impaired ubiquitinproteasome system (UPS) could lead to negative consequences for protein regulation, including loss of function. Another pivotal mechanism for the prevention of misfolded protein accumulation is the utilization of molecular chaperones. Molecular chaperones, such as heat shock proteins (HSPs) and FK506-binding proteins (FKBPs), are highly involved in protein regulation to ensure proper folding and normal function. In this review, we elaborate on the molecular basis of AD pathophysiology using recent data, with a particular focus on the role of the UPS and molecular chaperones as the defensive mechanism against misfolded proteins that have prion-like properties. In addition, we propose a rational therapy approach based on this mechanism.
Protein aggregation and degradation mechanisms in neurodegenerative diseases
American Journal of Neurodegenerative Disease, 2013
Neurodegenerative diseases are characterized by selective neuronal vulnerability and neurodegeneration in specific brain regions. The pathogenesis of these disorders centrally involves abnormal accumulation and aggregation of specific proteins, which are deposited in intracellular inclusions or extracellular aggregates that are characteristic for each disease. Increasing evidence suggests that genetic mutations or environmental factors can instigate protein misfolding and aggregation in these diseases. Consequently, neurodegenerative diseases are often considered as conformational diseases. This idea is further supported by studies implicating that impairment of the protein quality control (PQC) and clearance systems, such as the ubiquitin-proteasome system and autophagosome-lysosome pathway, may lead to the abnormal accumulation of disease-specific proteins. This suggests that similar pathological mechanisms may underlie the pathogenesis of the different neurodegenerative disorders. Interestingly, several proteins that are known to associate with neurodegenerative diseases have been identified as important regulators of PQC and clearance systems. In this review, we summarize the central features of abnormal protein accumulation in different common neurodegenerative diseases and discuss some aspects of specific disease-associated proteins regulating the PQC and clearance mechanisms, such as ubiquilin-1.
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
Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases
The ubiquitin proteasome system (UPS) is the primary proteolytic quality control system in cells and has an essential function in the nervous system. UPS dysfunction has been linked to neurodegenerative conditions, including Alzheimer’s, Parkinson’s and Huntington’s diseases. The pathology of neurodegenerative diseases is characterized by the abnormal accumulation of insoluble protein aggregates or inclusion bodies within neurons. The failure or dysregulation of the UPS prevents the degradation of misfolded/aberrant proteins, leading to deficient synaptic function that eventually affects the nervous system. In this review, we discuss the UPS and its physiological roles in the nervous system, its influence on neuronal function, and how UPS dysfunction contributes to the development of neurodegenerative diseases.
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
2013
Protein misfolding and aggregation are associated with many neurodegenerative diseases, including Huntington's disease. The cellular machinery for maintaining proteostasis includes molecular chaperones that facilitate protein folding and reduce proteotoxicity. Increasing the protein folding capacity of cells through manipulation of DNAJ chaperones has been shown to suppress aggregation and ameliorate polyglutamine toxicity in cells and flies. However, to date these promising findings have not been translated to mammalian models of disease. To address this issue, we developed transgenic mice that over-express the neuronal chaperone HSJ1a (DNAJB2a) and crossed them with the R6/2 mouse model of Huntington's disease. Over-expression of HSJ1a significantly reduced mutant huntingtin aggregation and enhanced solubility. Surprisingly, this was mediated through specific association with K63 ubiquitylated, detergent insoluble, higher order mutant huntingtin assemblies that decreased their ability to nucleate further aggregation. This was dependent on HSJ1a client binding ability, ubiquitin interaction and functional cooperation with HSP70. Importantly, these changes in mutant huntingtin solubility and aggregation led to improved neurological performance in R6/2 mice. These data reveal that prevention of further aggregation of detergent insoluble mutant huntingtin is an additional level of quality control for late stage chaperone-mediated neuroprotection. Furthermore, our findings represent an important proof of principle that DNAJ manipulation is a valid therapeutic approach for intervention in Huntington's disease.
Molecular chaperones in protein folding and proteostasis
Nature, 2011
P roteins are the most versatile and structurally complex biological macromolecules. They are involved in almost every biological process. Mammalian cells typically express in excess of 10,000 different protein species, which are synthesized on ribosomes as linear chains of up to several thousand amino acids. To function, these chains must generally fold into their 'native state' , an ensemble of a few closely related three-dimensional structures 1,2. How this is accomplished and how cells ensure the conformational integrity of their proteome in the face of acute and chronic challenges constitute one of the most fundamental and medically relevant problems in biology. Central to this problem is that proteins must retain conformational flexibility to function, and thus are only marginally thermodynamically stable in their physiological environment. A substantial fraction of all proteins in eukaryotic cells (20-30% of the total in mammalian cells) even seem to be inherently devoid of any ordered three-dimensional structure and adopt folded conformations only after interaction with binding partners 3. Aberrant behaviour of some of these metastable proteins, such as tau and α-synuclein, can give rise to the formation of fibrillar aggregates that are associated with dementia and Parkinson's disease. Thus, protein quality control and the maintenance of proteome homeostasis (known as proteostasis) are crucial for cellular and organismal health. Proteostasis is achieved by an integrated network of several hundred proteins 4 , including, most prominently, molecular chaperones and their regulators, which assist in de novo folding or refolding, and the ubiquitin−proteasome system (UPS) and autophagy system, which mediate the timely removal of irreversibly misfolded and aggregated proteins. Deficiencies in proteostasis have been shown to facilitate the manifestation or progression of numerous diseases, such as neurodegeneration and dementia, type 2 diabetes, peripheral amyloidosis, lysosomal storage disease, cystic fibrosis, cancer and cardiovascular disease. A major risk factor for many of these ailments is advanced age. Indeed, studies in model organisms indicate that ageing is linked to a gradual decline in cellular proteostasis capacity 5,6. Here we discuss recent insights into the mechanisms of chaperoneassisted protein folding and proteome maintenance. We focus on how proteins use the chaperone machinery to navigate successfully the complex folding-energy landscape in the crowded cellular environment. Understanding these reactions will guide future efforts to define the proteostasis network as a target for pharmacological intervention in diseases of aberrant protein folding.