BioMol Concepts 2018; 9: 94–102 Review Open Access Nikos Kourtis, Nektarios Tavernarakis* Small heat shock proteins and neurodegeneration: recent developments Journal xyz 2017; 1 (2): 122–135 https://doi.org/10.1515/bmc-2018-0009 received April 18, 2018; accepted June 25, 2018. (proteostasis). An evolutionary conserved cytoprotective The First Decade (1964-1972) mechanism is the heat shock response pathway [1, 2]. Abstract: Members of the small heat shock protein (sHSP) Prominent effectors of the heat shock response pathway family are molecularResearch chaperones Article with a critical role in the are molecular chaperones, which comprise of several maintenance of cellular homeostasis under unfavorable families categorized according to their molecular weight: conditions. MaxThe Musterman,chaperone properties Paul Placeholder of sHSPs HSP10, HSP40, HSP60, HSP70, HSP90, HSP100 and sHSP. prevent protein aggregation, and sHSP deregulation Chaperones are required for the maintenance of the native underlies theWhat pathology Is of So several Different diseases, including About structure of cellular proteins, protein translocation, neurodegenerativeNeuroenhancement? disorders. Recent evidence suggests assembly of functional protein complexes and protein that the clientele of sHSPs is broad, and the mechanisms of degradation. sHSPs are ATP-independent molecular sHSP-mediatedWas neuroprotection ist so andersdiverse. Nonetheless, am Neuroenhancement? the chaperones characterized by a small molecular mass crosstalk of sHSPs with the neurodegeneration-promoting ranging from 12 to 42 kDa [3] and a highly conserved signaling pathwaysPharmacological remains poorly and understood. Mental Here, Self-transformation we domain, called in the Ethic alpha-crystallin domain [4]. sHSPs survey recentComparison findings on the role and regulation of sHSPs display a dynamic behavior, and can exist in the form in neurodegenerativePharmakologische diseases. und mentale Selbstveränderungof monomers, dimers im and large multimeric complexes, exhibiting variability in subunit numbers (12 to >48) [5-7]. ethischen Vergleich Keywords: Alzheimer’s disease; Apoptosis; Heat sHSPs have a wide clientele and sHSP dysfunction shock response; Huntington’s disease; Inflammation; results in a broad range of pathologies, including https://doi.org/10.1515/xyz-2017-0010 Neurodegenerative pathologies; Parkinson’s disease; ischemia, myopathies, motor neuron disease, diabetes received February 9, 2013; accepted March 25, 2013; published online July 12, 2014 Protein aggregation; Proteostasis; sHSP. and cataracts [8-11]. The main function of sHSPs is Abstract: In the concept of the aesthetic formationto bind of knowledge to hydrophobic and its asregions soon of aggregation-prone as possible and success-oriented application, misfoldedinsights and proteins profits withoutand prevent the the formation of Introductionreference to the arguments developed around 1900.insoluble The mainaggregates investigation [12]. However,also association with includes the period between the entry into force andsHSPs the does presentation not lead in to its substrate current refolding to the native Organisms andversion. cells Theirare constantly function as exposed part of theto variousliterary portrayalstate [13-15]. and narrative Therefore, technique. the sHSP/substrate complexes act types of stress, such as environmental, metabolic or as intermediates that are further processed by the HSP70 Keywords: Function, transmission, investigation, principal, period pathophysiological stress. These disturbances result in and HSP90 chaperones [16-18]. Here, we highlight recent loss of integrity of the proteome, cellular dysfunction findings regarding the interplay between sHSP function Dedicated to Paul Placeholder and cell death. In the course of evolution, elaborate and neurodegeneration. molecular mechanisms were invented to counteract the detrimental effect of extrinsic and intrinsic stress factors on protein function,1 Studies and preserve and Investigationsprotein homeostasis The role of sHSPs in neurodegene- The main investigation also includes the periodrative between thepathologies entry into force and the presentation in its current version. Their function as part of the literary por- *Corresponding author: Nektarios Tavernarakis, Institute of trayal and narrative technique. Many devastating neurological disorders, such as Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Heraklion 70013, Crete, Greece; Department of Alzheimer’s, Parkinson’s, Creutzfeldt Jacobs and Basic Sciences, Faculty of Medicine, University of Crete, Heraklion amyotrophic lateral sclerosis (ALS), are characterized 71003, Crete, Greece,*Max Musterman:E-mail: [email protected] Institute of Marine Biology, National Taiwanby aggregation Ocean University, and 2 Pei-Ningprecipitation of misfolded proteins. Nikos Kourtis: DepartmentRoad Keelung of Pathology20224, Taiwan and Laura(R.O.C), and e-mail: Isaac [email protected] are key players of the proteostasis network, and Perlmutter CancerPaul Center, Placeholder: NYU School Institute of Medicine, of Marine New Biology, York, NationalNY Taiwantheir Oceanability University, to interact 2 Pei-Ning with aggregation-prone proteins 10016, USA Road Keelung 20224, Taiwan (R.O.C), e-mail: [email protected] Journal xyz 2017; 1 (2): 122–135 Open Access. © Open 2018 Access. Nikos © Kourtis, 2017 Mustermann Nektarios Tavernarakis,and Placeholder, published published by by De De Gruyter.Gruyter. This work work is is licensed under the Creative Commons Attribution-NonCommercial-NoDerivativeslicensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. 4.0 License. The First Decade (1964-1972) Research Article Max Musterman, Paul Placeholder What Is So Different About Neuroenhancement? Was ist so anders am Neuroenhancement? Pharmacological and Mental Self-transformation in Ethic Comparison Pharmakologische und mentale Selbstveränderung im ethischen Vergleich https://doi.org/10.1515/xyz-2017-0010 received February 9, 2013; accepted March 25, 2013; published online July 12, 2014 Abstract: In the concept of the aesthetic formation of knowledge and its as soon as possible and success-oriented application, insights and profits without the reference to the arguments developed around 1900. The main investigation also includes the period between the entry into force and the presentation in its current version. Their function as part of the literary portrayal and narrative technique. Keywords: Function, transmission, investigation, principal, period Dedicated to Paul Placeholder 1 Studies and Investigations The main investigation also includes the period between the entry into force and the presentation in its current version. Their function as part of the literary por- trayal and narrative technique. *Max Musterman: Institute of Marine Biology, National Taiwan Ocean University, 2 Pei-Ning Road Keelung 20224, Taiwan (R.O.C), e-mail: [email protected] Paul Placeholder: Institute of Marine Biology, National Taiwan Ocean University, 2 Pei-Ning Road Keelung 20224, Taiwan (R.O.C), e-mail: [email protected] Open Access. © 2017 Mustermann and Placeholder, published by De Gruyter. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. sHSPs in neurodegeneration 95 highlights the therapeutic potential of these heat shock for glial fibrillary acidic protein (GFAP). In AxD mouse proteins [19]. The deposition of fibrillar α-Synuclein models, overexpression of HSPB5 has a protective effect (α-syn) into inclusion bodies in the neuronal cell body or [37] and restores the defective proteasomal degradation processes is a pathological hallmark of neurodegenerative of mutant GFAP [38], suggesting that this sHSP may disorders, collectively known as synucleinopathies [20]. serve as a therapeutic target in astropathology. In spinal The expression of sHSPs is significantly increased in and bulbar muscular atrophy, a disease characterized the presence of cellular stress [21], and sHSPs have been by abnormally long polyglutamine tract (polyQ) in colocalized with α-syn in inclusion bodies [22, 23]. The mutant androgen receptor (ARpolyQ), HSPB8 promotes capacity of sHSPs to prevent α-syn aggregation depends motorneuron survival of patients by restoring autophagic on the kinetics of the aggregation process. Factors that flux and removing misfolded aggregates of ARpolyQ [39]. increase the rate of aggregation, such as disease-related Charcot-Marie-Tooth (CMT) is the most common mutations, gene amplification, or macromolecular inherited peripheral neuropathy. Missense mutations crowding, may alter the kinetics of α-syn aggregation in HSPB8 and HSPB1 have been implicated in CMT in cells, thus overwhelming the protective capacity pathogenesis [40-42]. HSPB8 knockout mice are viable of sHSPs due to reduced availability of aggregation- and display normal locomotor performances [43]. The combating chaperone subunits [24, 25]. HSPB1 (known list of mutations affecting the function of these sHSPs also as HSP27) binds along the surface of α-syn fibrils continues to grow [44, 45]. Transgenic mice expressing and inhibits their growth by blocking elongation [26]. In mutant HSPB1 developed features of CMT [46, 47] and addition to HSPB1, HSPB5 (αB-crystallin) also reduces displayed decreased a-tubulin acetylation and defective the aggregation of α-syn in in vitro assays [27]. Another axonal transport of mitochondria [46]. Intriguingly,