Small heat shock proteins and neurodegeneration: recent developments (original) (raw)
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Heat shock proteins in neurodegenerative diseases: Pathogenic roles and therapeutic implications
International Journal of Hyperthermia, 2009
Neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and polyglutamine (polyQ) diseases are thought to be caused by protein misfolding. Heat shock proteins (HSPs), which function mainly as molecular chaperones, play an important role in the folding and quality control of proteins. The histopathological hallmark of neurodegenerative diseases is accumulation and/or inclusions of the disease-causing proteins in residual neurons in targeted regions of the nervous system. The inclusions combine with many components of molecular chaperone pathways and ubiquitin-proteasome, raising the possibility that misfolding and altered degradation of mutant proteins may be involved in the pathogenesis of neurodegenerative diseases. Overexpression of HSPs has been reported to reduce the number and size of inclusions and accumulation of disease-causing proteins, and ameliorate the phenotypes in neuronal cell and mouse models. Hsp90 inhibitors also exert therapeutic effects through selective proteasome degradation of its client proteins. Elucidation of its pathophysiology using animal models has led to the development of disease-modifying drugs, i.e., Hsp90 inhibitor and HSP inducer, which inhibit the pathogenic process of neuronal degeneration. These findings may provide the basis for development of an HSP-related therapy for neurodegenerative diseases.
Molecular and cellular biochemistry, 2014
A number of acute and chronic neurodegenerative disorders are caused due to misfolding and aggregation of many intra- and extracellular proteins. Protein misfolding and aggregation processes in cells are strongly regulated by cellular molecular chaperones known as heat-shock proteins (Hsps) that include Hsp60, Hsp70, Hsp40, and Hsp90. Recent studies have shown the evidences that Hsps are colocalized in protein aggregates in Alzheimer's disease (AD), Parkinson's disease (PD), Polyglutamine disease (PGD), Prion disease, and other neurodegenerative disorders. This fact indicates that Hsps might have attempted to prevent aggregate formation in cells and thus to suppress disease conditions. Experimental findings have already established in many cases that selective overexpression of Hsps like Hsp70 and Hsp40 prevented the disease progression in various animal models and cellular models. However, recently, various Hsp modulators like geldanamycin, 17-(dimethylaminoethylamino)-17-d...
The Small Heat-Shock Proteins: Cellular Functions and Mutations Causing Neurodegeneration
Folding for the Synapse, 2010
Small heat-shock proteins (small Hsps) are a family of highly conserved proteins involved in multiple cellular mechanisms. Apart from their central role as chaperones in protecting cells during stressful conditions (as outlined in the previous two chapters), small Hsps also function to maintain cellular homeostasis in physiological conditions. Correct protein refolding to avoid aggregation, targeting misfolded proteins for degradation, proper cytoskeletal organization, and anti-apoptotic functions are some of the extensively studied attributes of small Hsps. One or more of these cellular mechanisms may malfunction in specific sets of neurons leading to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, polyglutamine disorders, and amyotrophic lateral sclerosis. Many in vitro models of these diseases have demonstrated the beneficial roles of small Hsps pointing out their protective role in attenuating the neurodegenerative phenotype. Interestingly, mutations in small Hsps themselves were linked to other degenerative disorders like inherited peripheral neuropathies and familial myopathies. Although not much is known regarding the exact patho-mechanism ("loss of function" or "gain of function") of mutations in causing disease, these discoveries reiterate the importance of small Hsps in maintaining neuronal health and indicate that the small Hsp family of proteins might have more functions than meets the eye. This chapter reviews the current knowledge regarding these enigmatic proteins, including their structure and function and how mutations in these once "forgotten proteins" might alter their functions and cause neurodegeneration. (2008) Asymmetrical late onset motor neuropathy associated with a novel mutation in the small heat shock protein HSPB1 (HSP27). J Neurol Neurosurg Psychiatry 79:461-463 Kalwy S A, Akbar M T, Coffin R S et al (2003) Heat shock protein 27 delivered via a herpes simplex virus vector can protect neurons of the hippocampus against kainic-acid-induced cell loss. Brain Res Mol Brain Res 111:91-103 Kasakov A S, Bukach O V, Seit-Nebi A S et al (2007) Effect of mutations in the beta5-beta7 loop on the structure and properties of human small heat shock protein HSP22 (HspB8, H11). FEBS J 274:5628-5642 Katsanis N, Beales P L, Woods M O et al (2000) Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nat Genet 26:67-70 Kamradt M C, Chen F, Cryns V L (2001) The small heat shock protein alpha B-crystallin negatively regulates cytochrome c-and caspase-8-dependent activation of caspase-3 by inhibiting its autoproteolytic maturation. J Biol Chem 276:16059-63 Kamradt M C, Chen F, Sam S et al (2002) The small heat shock protein alpha B-crystallin negatively regulates apoptosis during myogenic differentiation by inhibiting caspase-3 activation. J Biol Chem 277:38731-6 Kamradt M C, Lu M, Werner M E et al (2005) The small heat shock protein alpha B-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3. J Biol Chem 280:11059-66 Kijima K, Numakura C, Goto T et al (2005) Small heat shock protein 27 mutation in a Japanese patient with distal hereditary motor neuropathy. J Hum Genet 50:473-476 Kim K K, Kim R and Kim S H (1998) Crystal structure of a small heat-shock protein. Nature 394:595-599
The Protective and Therapeutic Function of Small Heat Shock Proteins in Neurological Diseases
Frontiers in Immunology, 2012
Historically, small heat shock proteins (sHSPs) have been extensively studied in the context of being intracellular molecular chaperones. However, recent studies looking at the role of sHSPs in neurological diseases have demonstrated a near universal upregulation of certain sHSPs in damaged and diseased brains. Initially, it was thought that sHSPs are pathological in these disease states because they are found in the areas of damage. However, transgenic overexpression and exogenous administration of sHSPs in various experimental disease paradigms have shown just the contrary -that sHSPs are protective, not pathological. This review examines sHSPs in neurological diseases and highlights the potential for using these neuroprotective sHSPs as novel therapeutics. It first addresses the endogenous expression of sHSPs in a variety of neurological disorders. Although many studies have examined the expression of sHSPs in neurological diseases, there are no review articles summarizing these data. Furthermore, it focuses on recent studies that have investigated the therapeutic potential of sHSPs for neurological diseases. Finally, it will explain what we think is the function of endogenous sHSPs in neurological diseases.
Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting
International Journal of Molecular Sciences, 2018
Among diseases whose cure is still far from being discovered, Alzheimer’s disease (AD) has been recognized as a crucial medical and social problem. A major issue in AD research is represented by the complexity of involved biochemical pathways, including the nature of protein misfolding, which results in the production of toxic species. Considering the involvement of (mis)folding processes in AD aetiology, targeting molecular chaperones represents a promising therapeutic perspective. This review analyses the connection between AD and molecular chaperones, with particular attention toward the most important heat shock proteins (HSPs) as representative components of the human chaperome: Hsp60, Hsp70 and Hsp90. The role of these proteins in AD is highlighted from a biological point of view. Pharmacological targeting of such HSPs with inhibitors or regulators is also discussed.
Neurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ) proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease.
Small heat shock proteins: multifaceted proteins with important implications for life
Cell Stress and Chaperones, 2019
Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archaea, bacteria, and eukaryota. sHSPs belong to the superfamily of molecular chaperones: they are components of the cellular protein quality control machinery and are thought to act as the first line of defense against conditions that endanger the cellular proteome. In plants, sHSPs protect cells against abiotic stresses, providing innovative targets for sustainable agricultural production. In humans, sHSPs (also known as HSPBs) are associated with the development of several neurological diseases. Thus, manipulation of sHSP expression may represent an attractive therapeutic strategy for disease treatment. Experimental evidence demonstrates that enhancing the chaperone function of sHSPs protects against age-related protein conformation diseases, which are characterized by protein aggregation. Moreover, sHSPs can promote longevity and healthy aging in vivo. In addition, sHSPs have been implicated in the prognosis of several types of cancer. Here, sHSP upregulation, by enhancing cellular health, could promote cancer development; on the other hand, their downregulation, by sensitizing cells to external stressors and chemotherapeutics, may have beneficial outcomes. The complexity and diversity of sHSP function and properties and the need to identify their specific clients, as well as their implication in human disease, have been discussed by many of the world's experts in the sHSP field during a dedicated workshop in Québec City, Canada, on 26-29 August 2018.
Heat Shock Protein 70 and Molecular Confession During Neurodegeneration
HSP70 in Human Diseases and Disorders, 2018
Molecular chaperones are the group of proteins that participate in the maintenance of cellular homeostasis by regulating several cellular events and protein homeostasis (proteostasis). It has been shown that failure of protein quality control system, formation of protein aggregates and their ectopic accumulation in the neuronal cells is the common pathological hallmark of most of the neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease (HD), Amyotrophic Lateral Sclerosis (ALS), prion disease and various forms of spinocerebellar ataxia (SCA) etc. Heat shock protein 70 (Hsp70), an evolutionary conserved protein family has been shown to be a key regulator in several neurodegenerative diseases. Hsp70 shows its strong expression in stress condition and is associated with protein folding, refolding of misfolded protein, transport of proteins to different cellular compartments, cell death and cell cycle regulation etc. Several recent studies have suggested that Hsp70 can be a key molecule to address the major pathologies associated with neurodegenerative diseases. This chapter briefly summarizes the Hsp70 and its possible role during neurodegenerative diseases.
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