Crosstalk Between Chaperone-Mediated Protein Disaggregation and Proteolytic Pathways in Aging and Disease

Abstract

A functional protein quality control machinery is crucial to maintain cellular and organismal physiology. Perturbation in the protein homeostasis network can lead to the formation of misfolded and aggregated proteins that are a hallmark of protein conformational disorders and aging. Protein aggregation is counteracted by the action of chaperones that can resolubilize aggregated proteins. An alternative protein aggregation clearance strategy is the elimination by proteolysis employing the ubiquitin proteasome system (UPS) or autophagy. Little is known how these three protein aggregate clearance strategies are regulated and coordinated in an organism with the progression of aging or upon expression of disease-associated proteins. To unravel the crosstalk between the protein aggregate clearance options, we investigated how autophagy and the UPS respond to perturbations in protein disaggregation capacity. We found that autophagy is induced as a potential compensatory mechanism, whereas the UPS exhibits reduced capacity upon depletion of disaggregating chaperones in C. elegans and HEK293 cells. The expression of amyloid proteins Aβ3–42 and Q40 result in an impairment of autophagy as well as the UPS within the same and even across tissues. Our data indicate a tight coordination between the different nodes of the proteostasis network (PN) with the progression of aging and upon imbalances of the capacity of each clearance mechanism.

Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in C. elegans

“…Additionally, Chapin et al reported that both basal autophagy as well as stress-induced autophagy can vary in different tissues [ 30 ]. Recently, it was shown that affecting proteostasis through the downregulation of chaperones involved in disaggregation results in increased autophagy and decreased UPS in C. elegans and human HEK293 cells [ 45 ]. Interestingly, the same study revealed that both autophagy and UPS are impaired in tissues expressing the human disease-linked amyloid protein Aβ 3–42 and Q 40 in C. elegans [ 45 ].…”

“…Recently, it was shown that affecting proteostasis through the downregulation of chaperones involved in disaggregation results in increased autophagy and decreased UPS in C. elegans and human HEK293 cells [ 45 ]. Interestingly, the same study revealed that both autophagy and UPS are impaired in tissues expressing the human disease-linked amyloid protein Aβ 3–42 and Q 40 in C. elegans [ 45 ]. Here, we reveal that a widespread downregulation of distinct autophagy genes generates tissue-specific UPS responses.…”

Molecular Basis of Neuronal Autophagy in Ageing: Insights from Caenorhabditis elegans

“…Young adult animals expressing amyloid-β 3-42 or polyglutamine (Q 40 ) in neuronal cells show increased levels of LGG-1 and moderate increased levels of SQST-1 (sequestosome 1)/p62 via immunodetection, indicating impairment of autophagy [ 249 ]. Whether such an increase represents transcriptional induction of LGG-1 and SQST-1 was not examined.…”

Sub-stoichiometric Hsp104 regulates the genesis and persistence of self-replicable amyloid seeds of a yeast prion protein

“…The insufficiency of the disaggregases has been linked with the amyloid-promoting propensity and its fatal consequences. 18 A functional prion protein (Sup35) that is beneficial to yeast serves as an excellent model to develop the prion concept as well as to elucidate the role of disaggregases in the prion-like transmission of several disease-associated amyloids. This is due to the following reasons.…”