Relationship Between Chaperone Proteins, Protein Α-Synuclein Linked to Potential Development of Parkinson Disease

December 4, 2019
Matthew Gavidia

A disturbed relationship between chaperone proteins and the protein α-synuclein was linked to cell damage and the development of Lewy bodies, which are common in those diagnosed with Parkinson disease, according to study findings.

A disturbed relationship between chaperone proteins and the protein α-synuclein was linked to cell damage and the development of Lewy bodies, which are common in those diagnosed with Parkinson disease (PD), according to study findings published today in the journal Nature.

Currently, there are no distinguishable causes of PD, but it has become well accepted that the protein α-synuclein plays a chief role in the development of PD. When α-synuclein shows negative tendencies, it causes critical cell damage that can lead to the formation of Lewy bodies. In healthy cells, α-synuclein is always accompanied by chaperone proteins, which serve as molecular bodyguards that maintain the protein as transportable and available. However, when these assisting proteins fail to protect α-synuclein in human cells, risk of Lewy body formation heightens, subsequently raising the risk of PD.

Researchers sought to analyze the relationship between chaperone proteins and α-synuclein to distinguish where interaction occurs and its contribution to Lewy body development. In human cells, 30 to 40 of the molecular bodyguards can potentially interact with α-synuclein.

Utilizing novel NMR technology, the scientists found segments of α-synuclein that interact with the individual chaperones at the atomic level by measuring the attenuation of the NMR signal intensity and chemical-shift perturbations using two-dimensional spectroscopy. This process systematically discovered a specific pattern that determines the exact interaction site of α-synuclein with the assisting proteins:

  • A functional mechanism for the regulation of α-synuclein by chaperones in mammalian cells occurs through transient binding
  • Molecular chaperones bind to α-synuclein through a canonical motif, by recognizing intrinsic biophysical features at the N terminus and around Tyr39
  • Interaction is abrogated after inhibition of 2 major chaperones, and results in transient interactions of α-synuclein with cellular membranes and re-localization of α-synuclein to mitochondria

Lead study author Sebastian Hiller, PhD, professor of structural biology at the University of Basel, described the interaction as not a fixed, rigid interaction, but a “dynamic and constantly changing encounter,” said Hiller. Researchers found that when chemical modifications of α-synuclein occur, such as those seen in PD, chaperone binding is impaired, which inhibits their ability to be a molecular bodyguard. These exposed α-synuclein proteins can then relocalize and accumulate on the membrane of the mitochondria, gradually destroying cells in the process.

As Lewy bodies typical for PD consist of membrane fragments and α-synuclein, Hiller stressed the role of chaperones as much more than an assisting protein. “Chaperones do far more than just assist in protein folding. They control cellular processes by flexibly interacting with a variety of proteins and accompanying them like a shadow,” said Hiller. As PD is one of the most common neurodegenerative disorders, further research into molecular interactions, as well as chaperones and the maintenance of their function, is warranted in developing innovative therapies.

Reference

Burmann BM, Gerez JA, Matečko-Burmann I, et al. Regulation of α-synuclein by chaperones in mammalian cells. [published online December 4, 2019]. Nature. doi: 10.1038/s41586-019-1808-9.