Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States?

Abstract

The property of molecular chaperones to dissolve protein aggregates of Parkinson-related α-synuclein has been known for some time. Recent findings point to an even more active role of molecular chaperones preventing the transformation of α-synuclein into pathological states subsequently leading to the formation of Lewy bodies, intracellular inclusions containing protein aggregates as well as broken organelles found in the brains of Parkinson’s patients. In parallel, a short motif around Tyr39 was identified as being crucial for the aggregation of α-synuclein. Interestingly, this region is also one of the main segments in contact with a diverse pool of molecular chaperones. Further, it could be shown that the inhibition of the chaperone:α-synuclein interaction leads to a binding of α-synuclein to mitochondria, which could also be shown to lead to mitochondrial membrane disruption as well as the possible proteolytic processing of α-synuclein by mitochondrial proteases. Here, we will review the current knowledge on the role of molecular chaperones in the regulation of physiological functions as well as the direct consequences of impairing these interactions—i.e., leading to enhanced mitochondrial interaction and consequential mitochondrial breakage, which might mark the initial stages of the structural transition of α-synuclein towards its pathological states.

A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

“…The role of molecular chaperones in the regulation of the physiological function of SYN has been recently reviewed [24]. These interactions reduce the amount of free SYN in the cells and thus prevent its structural transition towards pathological states.…”

“…The inhibition of the chaperone-SYN interaction facilitates the binding of SYN forming amphipathic helix into the lipid bilayer of the mitochondria membrane leading to membrane disruption [24]. SYN interaction with mitochondria occurs at higher protein expression or impaired chaperone-SYN ratio; therefore, the pathological conditions result in the failing of its CMA-derived proteolytic degradations [24].…”

“…The inhibition of the chaperone-SYN interaction facilitates the binding of SYN forming amphipathic helix into the lipid bilayer of the mitochondria membrane leading to membrane disruption [24]. SYN interaction with mitochondria occurs at higher protein expression or impaired chaperone-SYN ratio; therefore, the pathological conditions result in the failing of its CMA-derived proteolytic degradations [24]. Therapeutic strategies aiming to increase the SYN degradation through activation of these clearance pathways have thus been deeply explored in order to re-establish physiological levels of the protein and prevent its accumulation in PD [25,42,43].…”

Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

“…Interestingly, this region is also one of the main segments in contact with a diverse pool of molecular chaperones. Furthermore, inhibition of the chaperone/ α -syn interaction leads to binding of α -syn to mitochondria resulting in mitochondrial membrane disruption [ 252 ]. Interestingly, nilotinib, a specific inhibitor of c-Abl kinase activity, induces α -syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of α -syn in the rat midbrains enhances c-Abl expression [ 252 ].…”

Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins

“…In the context of αS interactions, Burmann and co-workers [ 8 ] reviewed the crucial role of molecular chaperones in regulating their physiological functions as well as the pathological aspects. Moreover, the crucial interactions with mitochondria as well as the regulation by posttranslational modifications were elucidated to understand the mechanisms of αS aggregation in the pathological contexts leading to Parkinson’s disease and other synucleinopathies.…”