Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies.

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Pathogenic alpha-synuclein (asyn) aggregates characterize synucleinopathies, including Parkinson's disease.
• Early diagnosis is difficult due to heterogeneous clinical presentations in prodromal stages.
• Distinct asyn strains with variable morphologies and functions are hypothesized to cause clinical heterogeneity.

Approach:

• Hypothesize that changing cellular environments during brain-to-body propagation alter asyn aggregate strains.
• Review asyn strain characteristics across synucleinopathies in clinical and preclinical studies.
• Propose investigating asyn strain morphology changes during trans-synaptic spreading using seeding amplification assays.

Key Points:

• Cellular environment influences asyn aggregate strain morphology.
• Asyn pathology propagates along the brain-body axis.
• Seeding amplification assays show promise for differentiating synucleinopathies.

Conclusions:

• Altered asyn strain morphology during propagation may explain phenotypic variability.
• Investigating strain changes could enable early diagnosis of synucleinopathies.
• Early diagnosis offers a wider therapeutic window and potential for personalized medicine.