Secreted Chaperones in Neurodegeneration

Abstract

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.

The unhappy chaperone

“…Such roles are key for maintaining biological function, and chaperones are critical components of organisms ranging from bacteria to man. Chaperones have been found to counteract protein aggregation and to solubilise protein aggregates already formed (Parsell et al, 1994;Glover and Lindquist, 1998;Hageman et al, 2010), for recent reviews see (Zarrouchioti et al, 2017;Mogk et al, 2018;Nillegoda et al, 2018;Kampinga et al, 2019;Rosenzweig et al, 2019;Webster et al, 2019;Sinnige et al, 2020;Chaplot et al, 2020). Examples of chaperones that have been reported to inhibit different microscopic steps of amyloid formation in vivo or in vitro are HSP70 for tau (Kundel et al, 2018;Nachman et al, 2020), HSP70 and crystallins for α-synuclein (Dedmon et al, 2005;Luk, 2008;Gaspar et al, 2020), DNAJB6 and DNAJB8 for poly-Q peptides (Hageman et al, 2010;Gillis et al, 2013;Månsson et al, 2014a;Kakkar et al, 2016;Thiruvalluvan et al, 2020), DNAJB proteins, Brichos and clusterin for amyloid β peptide (Månsson et al, 2014b;Månsson et al, 2018;Cohen et al, 2015;Yerbury et al, 2007), and HSP70, DNAJ and BiP for IAPP (Chien et al 2010).…”

The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

“…Progression of several neurodegenerative diseases, prominently including tauopathies such as frontotemporal dementia (FTD) and Alzheimer's disease (AD), is driven by spreading of aggregate pathology across brain regions in a prion-like seeding mechanism [1][2][3][4][5] . Tau aggregate spreading involves the exposure of aggregate seeds to the extracellular milieu 6,7 , suggesting that extracellular protein quality control factors may modulate disease progression 8 . Clusterin (Clu; apolipoprotein J) is a ∼70 kDa glycoprotein with chaperone-like properties found abundantly in plasma and extracellular fluid [8][9][10] .…”

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

“…The predominant responsible and final mechanism cascades are well identified and described in detail [ 28 ]. Based on these findings, i.e., antiapoptotic, neuroprotective or oxidative stress reducing compounds, were successfully tested in experimental chronic neurodegenerative and inflammatory disease models [ 4 , 29 , 30 , 31 ] ( Figure 1 ).…”

“…No therapy has been approved yet. One reason for these failures may be that chronic neurodegenerative processes result from different heterogeneous, but each other complementing metabolic, pathological cascades (as examples for ground breaking research: [ 43 , 44 , 45 ] for review: [ 4 , 5 ]). All of them end up in neuronal cell death inducing events, such as apoptosis as the suicide programme of the cell [ 28 , 29 ].…”

“…They are characterized by a common pathophysiologic mechanism, which is aberrant protein aggregation. Well known neuropathological features are β-amyloid and tau-protein enrichment in AD and accumulation of misfolded α-synuclein in PD [ 4 , 5 ]. Incidence of these PNDs will further rise.…”