PMC:2039847 / 17515-21418 JSONTXT

{"project":"2_test","denotations":[{"id":"17917109-12491239-72590826","span":{"begin":258,"end":261},"obj":"12491239"},{"id":"17917109-12491239-72590827","span":{"begin":361,"end":364},"obj":"12491239"},{"id":"17917109-12059769-72590828","span":{"begin":702,"end":705},"obj":"12059769"},{"id":"17917109-10950306-72590829","span":{"begin":838,"end":841},"obj":"10950306"},{"id":"17917109-8566529-72590830","span":{"begin":1603,"end":1606},"obj":"8566529"},{"id":"17917109-9650070-72590831","span":{"begin":1757,"end":1760},"obj":"9650070"},{"id":"17917109-12820654-72590832","span":{"begin":1868,"end":1871},"obj":"12820654"},{"id":"17917109-1739128-72590833","span":{"begin":2089,"end":2092},"obj":"1739128"},{"id":"17917109-8171966-72590833","span":{"begin":2089,"end":2092},"obj":"8171966"},{"id":"17917109-8059604-72590833","span":{"begin":2089,"end":2092},"obj":"8059604"},{"id":"17917109-8277336-72590833","span":{"begin":2089,"end":2092},"obj":"8277336"},{"id":"17917109-16599941-72590834","span":{"begin":2166,"end":2169},"obj":"16599941"},{"id":"17917109-16485107-72590835","span":{"begin":2171,"end":2174},"obj":"16485107"},{"id":"17917109-1739128-72590836","span":{"begin":2343,"end":2346},"obj":"1739128"},{"id":"17917109-16635482-72590837","span":{"begin":2348,"end":2351},"obj":"16635482"},{"id":"17917109-9369246-72590837","span":{"begin":2348,"end":2351},"obj":"9369246"},{"id":"17917109-11068040-72590837","span":{"begin":2348,"end":2351},"obj":"11068040"},{"id":"17917109-12699953-72590838","span":{"begin":2467,"end":2470},"obj":"12699953"},{"id":"17917109-10448084-72590839","span":{"begin":2649,"end":2652},"obj":"10448084"},{"id":"17917109-16485107-72590840","span":{"begin":2839,"end":2842},"obj":"16485107"},{"id":"17917109-16635482-72590841","span":{"begin":2844,"end":2847},"obj":"16635482"},{"id":"17917109-14963027-72590842","span":{"begin":2957,"end":2960},"obj":"14963027"},{"id":"17917109-8059604-72590843","span":{"begin":3233,"end":3236},"obj":"8059604"},{"id":"17917109-11823645-72590844","span":{"begin":3238,"end":3241},"obj":"11823645"},{"id":"17917109-12421356-72590844","span":{"begin":3238,"end":3241},"obj":"12421356"},{"id":"17917109-1373027-72590844","span":{"begin":3238,"end":3241},"obj":"1373027"},{"id":"17917109-8280851-72590844","span":{"begin":3238,"end":3241},"obj":"8280851"},{"id":"17917109-12470839-72590845","span":{"begin":3482,"end":3485},"obj":"12470839"},{"id":"17917109-11718923-72590846","span":{"begin":3722,"end":3725},"obj":"11718923"}],"text":"Professional Chaperones\nHeat shock proteins (Hsp) are professional chaperones. They are highly conserved proteins constitutively expressed in most cells under normal conditions where they play a role in cellular metabolism and help normal folding processes [105]. In addition, during cell stress, they bind unfolded proteins to keep them in their native state [105]. Heat shock proteins can be divided into two different families based on size and function: classic Hsps such as Hsp100, Hsp90, Hsp70, Hsp60, and the small heat shock proteins (sHsps). Hsps with a molecular weight of 60 kD or more possess an ATP-binding site and are actively involved in the process of refolding of misfolded proteins [106]. Small Hsps, with a molecular weight of 40 kD or less, lack this ATP-binding site and assist the Hsps in their refolding function [107]. The role of Hsps in misfolded protein recognition and refolding is illustrated in Fig. 1.\nFig. 1 The role of heat shock proteins (Hsp) and small heat shock proteins (sHsps) in recognition and refolding of unfolded and misfolded proteins. Unfolded or misfolded proteins are recognized by Hsps and sHsps. Together with these unfolded or misfolded proteins, Hsps and sHsps form a complex. In addition, Hsps recover unfolded or misfolded proteins back to their native form using ATP. If unfolded or misfolded protein are not recognized by the Hsp/sHsps, these unfolded or misfolded proteins are capable of forming aggregates\n\nSmall Heat Shock Proteins\nSmall Hsps function as molecular chaperones that can prevent proteins from adopting an incorrect conformation [108]. The sHsp family is characterized by the presence of an α-crystallin domain, a stretch of 80–100 amino acids in the C terminal half of the proteins [109]. So far, the sHsp family comprises ten sHsps, including αB-crystallin, Hsp27, Hsp20, HspB8, and HspB2/B3 [110]. Although sHsps are predominantly expressed in muscle cells, several family members are also found in human brain.\nIn AD, αB-crystallin and Hsp27 are upregulated and expressed by astrocytes surrounding SPs and NFTs [111–114], whereas Hsp20, HspB2, and HspB8 colocalize with Aβ in SPs and CAA [115, 116]. Although αB-crystallin or Hsp27 do not colocalize with Aβ in SPs, direct interaction between Aβ and these sHsps in addition to Hsp20 and HspB8 has been demonstrated [111, 117–119]. In addition, high-affinity binding of αB-crystallin and Aβ has been observed in eye lenses from AD patients [120]. Furthermore, αB-crystallin is able to prevent mature Aβ fibril formation, retaining it in a non-fibrillar, but likely a protofibrillar state, which is highly toxic to neurons [121]. Recently, we demonstrated that αB-crystallin, Hsp20, and HspB8 inhibit Aβ-mediated toxicity towards cerebrovascular cells probably by preventing aggregation of Aβ at the cell surface [116, 117]. Others showed that Hsp27 directly binds to hyperphosphorylated tau, thereby protecting against cell death [122].\nHsps are involved in the formation and persistence of misfolded protein aggregates. They are upregulated in several neurodegenerative diseases, such as AD, Creutzfeldt–Jakob disease, and Parkinson’s disease probably as a reaction to the formation of misfolded proteins [113, 123–126]. However, despite of increased intracellular levels, they are unable to prevent accumulation of Aβ in AD possibly because of decreased chaperone activity. In aged rats, this was illustrated by a significant decrease of Hsp90 function [127], resulting in diminished hepatic chaperone capacity. Furthermore, the increasing amount of damaged or misfolded proteins as a result of defects in protein degradation might lead to a total decrease in chaperone activity in aged cells [128]. Thus, the state of misfolded protein recognition and repair systems, such as the (s)Hsp system, might be of great importance in the development of neurodegenerative diseases.\n"}