The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson's disease and Dementia with Lewy bodies. For example molecules of the chaperone machinery are often deposited in Lewy bodies.
A new publication describes a vicious cycle in which parts of a chaperone facilitate the accumulation of toxic α-synuclein, which induces proteostatic stress that itself leads to an increase in insoluble fragments of the chaperone.
Molecular chaperones (proteins that assist the conformational folding or unfolding of large proteins) play important roles in protein misfolding diseases. Heat shock proteins are chaperones that protect cells when stressed by elevated temperatures. Heat shock protein 90 (Hsp90) is one of the most common of those chaperone proteins.
In this new publication, authors from Canada, Brazil and Israel show that STI1, the Hsp90 co-chaperone (proteins that assist chaperones ) co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in phosphorylated α-synuclein in ubiquitin-positive inclusions in two mouse models of α-synuclein misfolding.
In Parkinson disease human brains, STI1 was increased, and in neurologically healthy brains, STI1 and α-synuclein location correlated. Nuclear Magnetic Resonance analyses revealed direct interaction of α-synuclein with STI1 and indicated that the STI1 domain ( a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest) TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of α-synuclein.
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.
In conclusion the authors' 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.