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.

In Pancreatic Adenocarcinoma Alpha-Synuclein Increases and Marks Peri-Neural Infiltration

“…Synucleins (syns) are a family of small, soluble, highly conserved proteins, which consist of α-syn, β-syn, and γ-syn [ 1 , 2 , 3 , 4 ]. A considerable amount of native α-syn quickly misfolds and aggregates through five to six repeats of amino acid motif occurring toward the N terminal [ 5 , 6 , 7 ]. These repeats produce the formation of conserved amphipathic A2-helices also characteristic of apolipoproteins, which mediate aggregation and reversible binding to membrane phospholipids.…”

“…These repeats produce the formation of conserved amphipathic A2-helices also characteristic of apolipoproteins, which mediate aggregation and reversible binding to membrane phospholipids. Although various cell functions of α-syn remain to be established, the protein is known to be involved in some neurodegenerative disorders [ 7 ]. In fact, α-syn is a major component of Lewy bodies [ 8 , 9 , 10 , 11 ] in Parkinson’s disease (PD), and it is often detected in Alzheimer’s disease [ 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Long-term inhibition of mutant LRRK2 hyper-kinase activity reduced mouse brain α-synuclein oligomers without adverse effects

“…Excessive accumulation of misfolded αSyn aggregates in the brain beyond normal ageing is a pathological feature of PD 50 . Native αSyn exists in equilibrium amongst various forms, including oligomers, protofibrils and larger fibrillar conformations 51 . Aberrant accumulation of αSyn in PD exacerbates the formation of toxic αSyn oligomeric species that are released and propagated either as free-floating molecules or via extracellular vesicles in human brains 50 , 52 .…”

Glutathione Depletion and MicroRNA Dysregulation in Multiple System Atrophy: A Review

“…Clinically, levodopa responsiveness is a supporting feature of PD while MSA is often unresponsive to levodopa [ 43 , 44 ]. MSA, PD, and other Lewy body diseases (LBD) form a group of synucleopathies characterized by pathologic aggregates of α-syn [ 45 ], mainly differing in the sites of α-syn aggregation in the brain. Glial cytoplasmic inclusions of α-syn are hallmarks of MSA while aggregates of α-syn in the perikarya and neurites of neurons are known as Lewy bodies and Lewy neurites, respectively, and are present in PD, PD with dementia and dementia with Lewy body [ 45 , 46 ].…”

“…MSA, PD, and other Lewy body diseases (LBD) form a group of synucleopathies characterized by pathologic aggregates of α-syn [ 45 ], mainly differing in the sites of α-syn aggregation in the brain. Glial cytoplasmic inclusions of α-syn are hallmarks of MSA while aggregates of α-syn in the perikarya and neurites of neurons are known as Lewy bodies and Lewy neurites, respectively, and are present in PD, PD with dementia and dementia with Lewy body [ 45 , 46 ]. Recently, accumulating evidence suggests the existence of distinct strains of α-syn, possibly because of genetic polymorphism or protein modification, and their association with different patterns of disease propagation and atrophic regions [ 47 ].…”