Glycated Alpha-Synuclein Assemblies Cause Distinct Parkinson's Disease Pathogenesis in Mice

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Alpha-synuclein (α-Syn) misfolding and aggregation are central to Parkinson's disease (PD) pathogenesis.
• Glycation, a process exacerbated by hyperglycemia and aging, is increasingly recognized as a factor in PD.
• The specific impact of α-Syn glycation on its pathological potential remains incompletely understood.

Purpose of the Study:

• To investigate the influence of glycation on α-Syn structure and pathogenicity.
• To compare the neurotoxic and neuroinflammatory effects of glycated α-Syn assemblies versus non-glycated α-Syn fibrils.
• To elucidate the role of advanced glycation end products (AGEs) and their receptor (RAGE) in glycation-induced PD pathology.

Main Methods:

• α-Syn was glycated using methylglyoxal (MGO).
• Biophysical characteristics of glycated and non-glycated α-Syn were analyzed.
• Injections of α-Syn assemblies into the mouse substantia nigra (SN) were performed.
• Neuromuscular function, anxiety, neuroinflammation, and RAGE accumulation were assessed.

Main Results:

• Glycation altered α-Syn's biophysical properties and inhibited typical β-sheet formation.
• Both glycated and non-glycated α-Syn assemblies induced dopaminergic neurodegeneration and neuroinflammation.
• Glycated α-Syn assemblies led to heightened neuroinflammation and increased RAGE accumulation.
• Mice injected with glycated α-Syn exhibited an earlier onset of neuromuscular deficits and anxiety.

Conclusions:

• Glycation of α-Syn generates distinct pathological entities compared to non-glycated fibrils.
• Glycated α-Syn contributes to Parkinson's disease pathology with an accelerated timeline of motor symptom onset.
• These findings highlight the potential contribution of hyperglycemia-induced α-Syn glycation to increased PD risk in diabetic populations.