The Concept of α-Synuclein Strains and How Different Conformations May Explain Distinct Neurodegenerative Disorders

Abstract

In the past few years, an increasing amount of studies primarily based on experimental models have investigated the existence of distinct α-synuclein strains and their different pathological effects. This novel concept could shed light on the heterogeneous nature of α-synucleinopathies, a group of disorders that includes Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, which share as their key-molecular hallmark the abnormal aggregation of α-synuclein, a process that seems pivotal in disease pathogenesis according to experimental observations. However, the etiology of α-synucleinopathies and the initial events leading to the formation of α-synuclein aggregates remains elusive. Hence, the hypothesis that structurally distinct fibrillary assemblies of α-synuclein could have a causative role in the different disease phenotypes and explain, at least to some extent, their specific neurodegenerative, disease progression, and clinical presentation patterns is very appealing. Moreover, the presence of different α-synuclein strains might represent a potential biomarker for the diagnosis of these neurodegenerative disorders. In this regard, the recent use of super resolution techniques and protein aggregation assays has offered the possibility, on the one hand, to elucidate the conformation of α-synuclein pathogenic strains and, on the other hand, to cyclically amplify to detectable levels low amounts of α-synuclein strains in blood, cerebrospinal fluid and peripheral tissue from patients. Thus, the inclusion of these techniques could facilitate the differentiation between α-synucleinopathies, even at early stages, which is crucial for successful therapeutic intervention. This mini-review summarizes the current knowledge on α-synuclein strains and discusses its possible applications and potential benefits.

Keywords: biomarker; experimental models; strains; α-synuclein; α-synucleinopathies.

Figure 1

Schematic overview including the main pathological features of prodromal and classical α-synucleinopathies. The combination of novel structural and biochemical analyses have demonstrated the existence of different α-syn strains in classical α-synucleinopathies (PD, DLB and MSA). Recent experimental data also indicate that distinct α-syn strains might be associated, not only with the affected cell type and type of α-syn inclusion (neuronal LBs vs. oligodendroglial GCIs), but also with the neurodegeneration pattern and disease severity. However, at present it is still unclear whether distinct α-syn strains are also associated with prodromal α-synucleinopathies, or if they only constitute early phases of classical α-synucleinopathies. Thus, pathological α-syn in PAF and iRBD patients could lead to the formation of LBs, GCIs and the extension of neuronal loss to other areas within the CNS. SND, striatonigral degeneration; OPCA, olivopontocerebellar atrophy. Created with BioRender.com.