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Basic Science and Pathogenesis.

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Area of Science:

  • Neuroscience
  • Neurodegenerative Diseases
  • Biomedical Imaging

Background:

  • Alpha-synucleinopathies, like Parkinson's disease, involve alpha-synuclein aggregation, dopaminergic neuron loss, and white matter changes.
  • Understanding the spatiotemporal relationship between these pathologies is crucial for modeling disease progression.
  • A mouse model was developed to investigate these interconnected pathological features.

Purpose of the Study:

  • To map the spatial-temporal association between alpha-synuclein (α-syn) inclusions, dopaminergic neurodegeneration, and white matter microstructural changes.
  • To utilize a mouse model of α-synucleinopathy for in-depth pathological analysis.
  • To correlate imaging findings with histological validation.

Main Methods:

  • Unilateral injection of pre-formed fibrils (PFFs) or monomeric α-synuclein into the substantia nigra pars compacta (SNc) of wild-type mice.
  • Ex vivo diffusion tensor imaging (DTI) MRI at 9.4 T to assess white matter structural connectivity at 12 and 20 weeks post-injection (wpi).
  • Light-sheet microscopy (LSM) to map α-synuclein aggregates (pS129) and dopaminergic neurodegeneration (tyrosine hydroxylase staining), validated by voxel-based analysis (VBA) and atlas-based analysis (ABA).

Main Results:

  • PFF injection induced dense α-synuclein pathology and dopaminergic neuron death in the SNc, with prion-like seeding and spread to the striatum.
  • Dopaminergic neurodegeneration correlated with dopaminergic denervation in the striatum.
  • DTI MRI revealed decreased fractional anisotropy in the corpus callosum and internal capsule, indicating structural connectivity changes associated with neurodegeneration.

Conclusions:

  • The α-synuclein PFF mouse model recapitulates key features of Parkinson's disease, including pathology, white matter impairment, and nigrostriatal degeneration.
  • Ex vivo MRI-LSM platform effectively visualizes pathology spread at circuit and whole-brain levels.
  • This integrated approach provides a powerful tool for studying α-synucleinopathies.