The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction

Abstract

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer’s disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.

Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-β deposition in a mouse model of Alzheimer’s disease

“…Furthermore, STI1/ Hop loss of function in Drosophila overexpressing the full-length 2 N/4R isoform of wild-type human tau in the eye, resulted in significant loss of retinal cells [107]. Recently, Inda et al [40] demonstrated that in AD, chaperones associate to form large stable complexes, termed epichaperomes, that no longer regulate client protein function. These epichaperomes impaired protein connectivity, proteostasis, and synaptic plasticity in their AD mouse models [40], which could be corrected by disassembly of epichaperomes by an Hsp90 inhibitor.…”

“…Recently, Inda et al [40] demonstrated that in AD, chaperones associate to form large stable complexes, termed epichaperomes, that no longer regulate client protein function. These epichaperomes impaired protein connectivity, proteostasis, and synaptic plasticity in their AD mouse models [40], which could be corrected by disassembly of epichaperomes by an Hsp90 inhibitor. Since Hsp90, Hsp70 and STI1 are all members of these epichaperomes in AD tissues, it may be important to test in the future how increased or decreased levels of STI1 regulate epichaperomes.…”

“…Molecular chaperones such as Hsp70 and Hsp90 also play critical roles in AD and other protein misfolding diseases [ 36 – 39 ]. In neurodegenerative diseases, there is considerable evidence that molecular chaperone complexes are altered [ 40 ] and Hsp90 inhibition in vivo reduced neuronal and synaptic loss due to amyloid toxicity in mice [ 41 ]. Moreover, blocking abnormal chaperome interactions have also been shown to improve tau toxicity [ 40 ].…”

Single cell transcriptomic profiling of neurodegeneration mediated by tau propagation in a novel 3D neuron-astrocyte coculture model

“…9). The inability of neurons to cope with accumulating tau pathology is hypothesized to stimulate formation of a dysfunctional epichaperome (high molecular weight complexes composed of HSP90 and HSP70 chaperones) and render neurons prone to degeneration 29 . The strong transcriptional response of HSPs in AstAD prompted us to test whether improving chaperone function by dispersing the dysfunctional epichaperome could delay disease progression.…”

Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity

“…For instance, epichaperomes, i.e. metastable chaperone networks stabilized by Hsp90, seem to promote the accumulation and toxicity of misfolded tau (21). Experiments using purified proteins have shown that Hsp90 has the capacity to both inhibit TDP-43 aggregation and to convert TDP-43 aggregates into more soluble species (22).…”