Small Heat Shock Proteins and Human Neurodegenerative Diseases

Muranova, Lydia K.; Ryzhavskaya, A S; Sudnitsyna, Maria V.; Shatov, Vladislav M.; Gusev, Nikolai B.

doi:10.1134/s000629791911004x

Cited by 34 publications

(30 citation statements)

References 89 publications

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“…The latter observation suggests that the mechanism of mutations located in the NTD on the overall structure and properties of sHsp heterooligomers may be rather complex. Beyond artificial mutations like the ones used here, this observation is also relevant for natural, abundantly observed disease-related mutations [30,43,44].…”

Section: Discussionmentioning

confidence: 84%

The Heterooligomerization of Human Small Heat Shock Proteins Is Controlled by Conserved Motif Located in the N-Terminal Domain

Shatov

Strelkov

Gusev

2020

IJMS

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Ubiquitously expressed human small heat shock proteins (sHsps) HspB1, HspB5, HspB6 and HspB8 contain a conserved motif (S/G)RLFD in their N-terminal domain. For each of them, we prepared mutants with a replacement of the conserved R by A (R/A mutants) and a complete deletion of the pentapeptide (Δ mutants) and analyzed their heterooligomerization with other wild-type (WT) human sHsps. We found that WT HspB1 and HspB5 formed heterooligomers with HspB6 only upon heating. In contrast, both HspB1 mutants interacted with WT HspB6 even at low temperature. HspB1/HspB6 heterooligomers revealed a broad size distribution with equimolar ratio suggestive of heterodimers as building blocks, while HspB5/HspB6 heterooligomers had an approximate 2:1 ratio. In contrast, R/A or Δ mutants of HspB6, when mixed with either HspB1 or HspB5, resulted in heterooligomers with a highly variable molar ratio and a decreased HspB6 incorporation. No heterooligomerization of HspB8 or its mutants with either HspB1 or HspB5 could be detected. Finally, R/A or Δ mutations had no effect on heterooligomerization of HspB1 and HspB5 as analyzed by ion exchange chromatography. We conclude that the conserved N-terminal motif plays an important role in heterooligomer formation, as especially pronounced in HspB6 lacking the C-terminal IXI motif.

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Section: Discussionmentioning

confidence: 84%

The Heterooligomerization of Human Small Heat Shock Proteins Is Controlled by Conserved Motif Located in the N-Terminal Domain

Shatov

Strelkov

Gusev

2020

IJMS

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“…Mutations in the BAG2-Hsc70 chaperone complex was found to cause synaptic vesicles, normally located in the axon, to appear in the spines and processes of dendrites (Fukuzono et al, 2016). Chaperones contribute a great deal to cytoskeletal stability, which is especially important for neurons to sustain their complex processes ( Table 2; Bakthisaran et al, 2015;Nefedova et al, 2015;Nefedova et al, 2017;Kelliher et al, 2019;Muranova et al, 2019;Vallin and Grantham, 2019;Muranova et al, 2020). Many chaperones are implicated specifically in axonal morphology: manipulation of several small heat shock proteins as well as Hsp70 and 90 was found to significantly decrease synapse number in Drosophila neuromuscular junctions (Santana et al, 2020), and an Hsp70 orthologue has been found to assist in polarized trafficking of synaptic vesicle proteins to axons (Fukuzono et al, 2016).…”

Section: Protein Maintenance In Dendritic Arborizationmentioning

confidence: 99%

Homeostatic Roles of the Proteostasis Network in Dendrites

Lottes

Cox

2020

Front. Cell. Neurosci.

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Cellular protein homeostasis, or proteostasis, is indispensable to the survival and function of all cells. Distinct from other cell types, neurons are long-lived, exhibiting architecturally complex and diverse multipolar projection morphologies that can span great distances. These properties present unique demands on proteostatic machinery to dynamically regulate the neuronal proteome in both space and time. Proteostasis is regulated by a distributed network of cellular processes, the proteostasis network (PN), which ensures precise control of protein synthesis, native conformational folding and maintenance, and protein turnover and degradation, collectively safeguarding proteome integrity both under homeostatic conditions and in the contexts of cellular stress, aging, and disease. Dendrites are equipped with distributed cellular machinery for protein synthesis and turnover, including dendritically trafficked ribosomes, chaperones, and autophagosomes. The PN can be subdivided into an adaptive network of three major functional pathways that synergistically govern protein quality control through the action of (1) protein synthesis machinery; (2) maintenance mechanisms including molecular chaperones involved in protein folding; and (3) degradative pathways (e.g., Ubiquitin-Proteasome System (UPS), endolysosomal pathway, and autophagy. Perturbations in any of the three arms of proteostasis can have dramatic effects on neurons, especially on their dendrites, which require tightly controlled homeostasis for proper development and maintenance. Moreover, the critical importance of the PN as a cell surveillance system against protein dyshomeostasis has been highlighted by extensive work demonstrating that the aggregation and/or failure to clear aggregated proteins figures centrally in many neurological disorders. While these studies demonstrate the relevance of derangements in proteostasis to human neurological disease, here we mainly review recent literature on homeostatic developmental roles the PN machinery plays in the establishment, maintenance, and plasticity of stable and dynamic dendritic arbors. Beyond basic housekeeping functions, we consider roles of PN machinery in protein quality control mechanisms linked to dendritic plasticity (e.g., dendritic spine remodeling during LTP); cell-type specificity; dendritic morphogenesis; and dendritic pruning.

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“…Next, the neural and endocrine-specific proteins, 7B2 and proSAAS, are discussed with respect to their potent anti-aggregant activity and association with neurodegenerative disease. We will then focus on extracellular actions of certain secreted small Hsps (sHsps); while sHsps have been extensively reviewed recently, most reviews in neurodegeneration have focused on their cytoplasmic actions ( Muranova et al, 2019 ; Webster et al, 2019 ). Finally, we will elaborate on possible biochemical and physiological mechanisms of extracellular chaperones and discuss their therapeutic potential in treating neurodegenerative disease.…”

Section: Introductionmentioning

confidence: 99%

Secreted Chaperones in Neurodegeneration

Chaplot

Jarvela

Lindberg

2020

Front. Aging Neurosci.

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Protein homeostasis, or proteostasis, is a combination of cellular processes that govern protein quality control, namely, protein translation, folding, processing, and degradation. Disruptions in these processes can lead to protein misfolding and aggregation. Proteostatic disruption can lead to cellular changes such as endoplasmic reticulum or oxidative stress; organelle dysfunction; and, if continued, to cell death. A majority of neurodegenerative diseases involve the pathologic aggregation of proteins that subverts normal neuronal function. While prior reviews of neuronal proteostasis in neurodegenerative processes have focused on cytoplasmic chaperones, there is increasing evidence that chaperones secreted both by neurons and other brain cells in the extracellular – including transsynaptic – space play important roles in neuronal proteostasis. In this review, we will introduce various secreted chaperones involved in neurodegeneration. We begin with clusterin and discuss its identification in various protein aggregates, and the use of increased cerebrospinal fluid (CSF) clusterin as a potential biomarker and as a potential therapeutic. Our next secreted chaperone is progranulin; polymorphisms in this gene represent a known genetic risk factor for frontotemporal lobar degeneration, and progranulin overexpression has been found to be effective in reducing Alzheimer’s- and Parkinson’s-like neurodegenerative phenotypes in mouse models. We move on to BRICHOS domain-containing proteins, a family of proteins containing highly potent anti-amyloidogenic activity; we summarize studies describing the biochemical mechanisms by which recombinant BRICHOS protein might serve as a therapeutic agent. The next section of the review is devoted to the secreted chaperones 7B2 and proSAAS, small neuronal proteins which are packaged together with neuropeptides and released during synaptic activity. Since proteins can be secreted by both classical secretory and non-classical mechanisms, we also review the small heat shock proteins (sHsps) that can be secreted from the cytoplasm to the extracellular environment and provide evidence for their involvement in extracellular proteostasis and neuroprotection. Our goal in this review focusing on extracellular chaperones in neurodegenerative disease is to summarize the most recent literature relating to neurodegeneration for each secreted chaperone; to identify any common mechanisms; and to point out areas of similarity as well as differences between the secreted chaperones identified to date.

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Small Heat Shock Proteins and Human Neurodegenerative Diseases

Cited by 34 publications

References 89 publications

The Heterooligomerization of Human Small Heat Shock Proteins Is Controlled by Conserved Motif Located in the N-Terminal Domain

The Heterooligomerization of Human Small Heat Shock Proteins Is Controlled by Conserved Motif Located in the N-Terminal Domain

Homeostatic Roles of the Proteostasis Network in Dendrites

Secreted Chaperones in Neurodegeneration

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