Alpha and Beta Synucleins: From Pathophysiology to Clinical Application as Biomarkers

Abstract

A BS TRACT: The synuclein family includes three neuronal proteins, named α-synuclein, β-synuclein, and γ-synuclein, that have peculiar structural features. α-synuclein is largely known for being a key protein in the pathophysiology of Parkinson's disease (PD) and other synucleinopathies, namely, dementia with Lewy bodies and multisystem atrophy. The role of β-synuclein and γ-synuclein is less well understood in terms of physiological functions and potential contribution to human diseases. α-synuclein has been investigated extensively in both cerebrospinal fluid (CSF) and blood as a potential biomarker for synucleinopathies. Recently, great attention has been also paid to β-synuclein, whose CSF and blood levels seem to reflect synaptic damage and neurodegeneration independent of the presence of synucleinopathy. In this review, we aim to provide an overview on the pathophysiological roles of the synucleins. Because γ-synuclein has been poorly investigated in the field of synucleinopathy and its pathophysiological roles are far from being clear, we focus on the interactions between α-synuclein and β-synuclein in PD. We also discuss the role of α-synuclein and β-synuclein as potential biomarkers to improve the diagnostic characterization of synucleinopathies, thus highlighting their potential application in clinical trials for disease-modifying therapies.

Cerebrospinal fluid β-synuclein as a synaptic biomarker for preclinical Alzheimer’s disease

“…We also observed increased CSF α-syn levels in pre-AD subjects, but not in MCI-AD and dem-AD. While α-syn has been variably reported increased in AD as a CSF biomarker of synaptic derangement, decreased α-syn levels may indicate the presence of α-synucleinopathy 9 18. In our cohort, we may speculate that the slight decrease of CSF α-syn along the AD continuum could partly depend on α-syn copathology, which is reported in nearly half of all AD cases 10.…”

“…Elevated CSF levels of both β-syn and α-syn may, hence, reflect the earliest synaptic dysfunction occurring in AD. Given that β-syn concentrations are not influenced by the presence of synucleinopathy nor by blood contamination, which instead affects α-syn measurements, CSF β-syn might be an even more robust synaptic biomarker than α-syn 9…”

“…Here, we aimed to investigate CSF β-syn levels in cognitively healthy subjects (non-degenerative neurological patients and subjects with subjective cognitive complaints) and in the whole AD continuum, including pre-AD cases. Given their close pathophysiological relationship, we compared CSF β-syn values with those of α-synuclein (α-syn), another synaptic protein that has been variably reported to be increased in AD 9–11. Moreover, we assessed two surrogate biomarkers of neuro-axonal degeneration, namely total tau protein (t-tau) and neurofilament light chain protein (NfL), in order to better describe the evolution of synaptic and neuronal damage in the AD continuum.…”

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 ].…”

Classical Cerebrospinal Fluid Biomarkers in Dementia with Lewy Bodies

“…Furthermore, worth noting is that recent findings have pointed out the potential role of the two members of the family of synucleins {α-synuclein (140 amino acids) and β-synuclein (134 amino acids) as biomarkers for the diagnostic characterization of patients affected by synucleinopathies as DLB [ 31 ].…”