S100A9 Alters the Pathway of Alpha-Synuclein Amyloid Aggregation.

Zigmantas Toleikis,Kristaps Jaudzems,Vytautas Smirnovas,Vytautas Petrauskas,Lina Baranauskiene,Mantas Ziaunys

doi:10.3390/ijms22157972

Abstract

The formation of amyloid fibril plaques in the brain creates inflammation and neuron death. This process is observed in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Alpha-synuclein is the main protein found in neuronal inclusions of patients who have suffered from Parkinson’s disease. S100A9 is a calcium-binding, pro-inflammation protein, which is also found in such amyloid plaques. To understand the influence of S100A9 on the aggregation of -synuclein, we analyzed their co-aggregation kinetics and the resulting amyloid fibril structure by Fourier-transform infrared spectroscopy and atomic force microscopy. We found that the presence of S100A9 alters the aggregation kinetics of -synuclein and stabilizes the formation of a particular amyloid fibril structure. We also show that the solution’s ionic strength influences the interplay between S100A9 and -synuclein, stabilizing a different structure of -synuclein fibrils.

Highlights

The formation of protein amyloid fibrils is related to neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease [1], as well as other amyloidoses [2]
We found that the presence of S100A9 alters the aggregation kinetics of α-synuclein and stabilizes the formation of a particular amyloid fibril structure
It was reported that the rate of fibril formation depends on the reaction solution pH value [17], ionic strength [18], and protein concentration [19], but it can be modulated by the presence of other amyloid proteins, such as Tau protein [20], amyloid beta peptide [21], prion protein [22,23,24], S100A9 [25] or non-amyloid proteins like serum albumin [26] and protein chaperon Hsc70 [27]

Summary

Introduction

The formation of protein amyloid fibrils is related to neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease [1], as well as other amyloidoses [2]. There are over 30 different amyloid-disease-related proteins and peptides [3], which have both highly distinct amino acid sequences and structural motifs. Upon aggregation, α-syn loses the physiological function and is found in large neuronal inclusions (known as Lewy bodies in Parkinson’s disease) or glial cytoplasmic inclusions (in multiple system atrophy) [9,10,11]. Due to the vast number of people affected by Parkinson’s disease, this protein has been the subject of numerous studies in vivo, in vitro and in silico that revealed several peculiar aspects of α-syn aggregation and fibril structure. It was reported that the rate of fibril formation depends on the reaction solution pH value [17], ionic strength [18], and protein concentration [19], but it can be modulated by the presence of other amyloid proteins, such as Tau protein [20], amyloid beta peptide [21], prion protein [22,23,24], S100A9 [25] or non-amyloid proteins like serum albumin [26] and protein chaperon Hsc70 [27]

Methods

Results

Discussion

Conclusion