The penalty of stress ‐ Epichaperomes negatively reshaping the brain in neurodegenerative disorders

Ginsberg, Stephen D.; Joshi, Suhasini; Sharma, Sahil; Guzman, Gianny; Wang, Tai; Arancio, Ottavio; Chiosis, Gabriela

doi:10.1111/jnc.15525

Cited by 22 publications

(16 citation statements)

References 147 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…STI1 is also one of the co-chaperones found to interact with α-synuclein in a proteomics analysis in cultured cells [ 21 ]. In response to proteostatic stress, the chaperone machinery (the chaperome) becomes abnormally connected, forming the epichaperome, which is deleterious for neuronal function [ 57 , 64 ]. STI1 is a critical epichaperome regulator and reducing the levels of STI1 collapsed the abnormal connectivity of the epichaperome in cancer cells [ 30 , 102 ].…”

Section: Introductionmentioning

confidence: 99%

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

et al. 2022

View full text Add to dashboard Cite

The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Molecular chaperones play important roles in protein misfolding diseases and members of the chaperone machinery are often deposited in Lewy bodies. Here, we show that the Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in insoluble protein fractions in two mouse models of α-synuclein misfolding. STI1 and Hsp90 also co-localized extensively with filamentous S129 phosphorylated α-synuclein in ubiquitin-positive inclusions. In PD human brains, STI1 transcripts were increased, and in neurologically healthy brains, STI1 and α-synuclein transcripts correlated. Nuclear Magnetic Resonance (NMR) analyses revealed direct interaction of α-synuclein with STI1 and indicated that the STI1 TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of α-synuclein. In vitro, the STI1 TPR2A domain facilitated S129 phosphorylation by Polo-like kinase 3. Moreover, mice over-expressing STI1 and Hsp90ß presented elevated α-synuclein S129 phosphorylation accompanied by inclusions when injected with α-synuclein pre-formed fibrils. In contrast, reduced STI1 function decreased protein inclusion formation, S129 α-synuclein phosphorylation, while mitigating motor and cognitive deficits as well as mesoscopic brain atrophy in α-synuclein-over-expressing mice. Our findings reveal a vicious cycle in which STI1 facilitates the generation and accumulation of toxic α-synuclein conformers, while α-synuclein-induced proteostatic stress increased insoluble STI1 and Hsp90.

show abstract

Section: Introductionmentioning

confidence: 99%

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Based on this, we hypothesized that pharmacological modulation by HSP90 inhibitor PU-H71 would validate the involvement of HSF1-driven HSP chaperones in AstTau pathogenesis. This hypothesis is supported by recent work that suggests a dysfunctional HSP chaperone system in disease can be ameliorated by PU-H71 through the production of more functional molecular chaperones (HSc70 and HSP90) as shown in 2D iPSC and mouse models of tauopathy 77 , 78 , 104 . We have now shown striking protection by PU-H71 treatment in the iPSC AstTau system that includes rescuing neurons from degeneration.…”

Section: Discussionmentioning

confidence: 60%

“…Chaperones are proteins that control neuronal function by regulating protein folding, thereby determining the functional levels and activities of many proteins 75 , 76 . Accumulating intracellular protein aggregates, such as misfolded tau, are thought to compete with functional endogenous proteins for binding to chaperones, creating dysfunctional, high molecular weight tau-chaperone complexes containing HSc70 and 90, rendering neurons prone to degeneration 77 , 78 . AstTau cultures were treated with HSP90 inhibitor PU-H71 (1 µM, 3 days), which has been shown to modulate the HSF1 transcriptional pathway, stimulating HSP chaperone production (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model

et al. 2022

View full text Add to dashboard Cite

The use of iPSC derived brain organoid models to study neurodegenerative disease has been hampered by a lack of systems that accurately and expeditiously recapitulate pathogenesis in the context of neuron-glial interactions. Here we report development of a system, termed AstTau, which propagates toxic human tau oligomers in iPSC derived neuron-astrocyte assembloids. The AstTau system develops much of the neuronal and astrocytic pathology observed in tauopathies including misfolded, phosphorylated, oligomeric, and fibrillar tau, strong neurodegeneration, and reactive astrogliosis. Single cell transcriptomic profiling combined with immunochemistry characterizes a model system that can more closely recapitulate late-stage changes in adult neurodegeneration. The transcriptomic studies demonstrate striking changes in neuroinflammatory and heat shock protein (HSP) chaperone systems in the disease process. Treatment with the HSP90 inhibitor PU-H71 is used to address the putative dysfunctional HSP chaperone system and produces a strong reduction of pathology and neurodegeneration, highlighting the potential of AstTau as a rapid and reproducible tool for drug discovery.

show abstract

“…The observed sugar-induced asymmetry in the conformations of this substructure provides further potential for the expansion of the ensembles of GRP94 conformations that can interact with different partners, supporting the role of the glycosylated chaperone as the hub for proteome-wide interaction perturbations. Overall, we suggest a picture whereby PTMs modulate the dynamics of the ATP-state as well as the efficiency of the catalytic hydrolysis cycle of the nucleotide, potentially providing a convenient mechanism of GRP94 adaptation to different cell conditions, in particular to chronic cellular stress states [64][65][66] , inducing extensive protein covalent modifications 10,67,68 .…”

Section: Discussionmentioning

confidence: 94%

How AberrantN-Glycosylation Can Alter Protein Functionality and Ligand Binding: an Atomistic View

Castelli

Yan

Rodina

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Protein assembly defects due to enrichment of aberrant conformational variants of proteins are emerging as a new frontier in therapeutics design. Understanding, atomistically, structural elements that remodel the energy landscape of proteins, with the consequence of rewiring the conformational dynamics of proteins and pathologically perturbing functionally-oriented ensembles, is key for development of inhibitors. This is particularly relevant for molecular chaperones, hub proteins for the assembly of large multiprotein complexes, where enrichment of aberrant conformers can have a large impact on the cellular proteome, and in turn, on phenotypes. Here, we integrate computational and experimental tools to unveil how N-glycosylation of specific residues in glucose-regulated protein 94 (GRP94) modulates internal dynamics and alters the conformational fitness of regions fundamental for interaction with the nucleotide and synthetic ligands, and impacts substructures dedicated to recognition of interacting proteins. We show how N-glycosylation plays an active role in modulating the energy landscape of the protein, with specific glycosylation patterns determining specific functionally-oriented dynamic signatures. Our results provide support for leveraging the structural-dynamics knowledge on distinct glycosylation variants to design molecules targeting GRP94 disease-associated conformational states and assemblies. Since glycosylation is the most abundant form of post-translational modification, our results and mechanistic models can readily be transferred to other targets and contexts for cancers and other diseases.

show abstract

The penalty of stress ‐ Epichaperomes negatively reshaping the brain in neurodegenerative disorders

Cited by 22 publications

References 147 publications

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model

How AberrantN-Glycosylation Can Alter Protein Functionality and Ligand Binding: an Atomistic View

Contact Info

Product

Resources

About