Alpha-synuclein-positive structures induced in leupeptin-infused rats

Area of Science:

• Neuroscience
• Pathology
• Biochemistry

Background:

• Abnormal alpha-synuclein accumulation is central to neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA).
• The precise mechanisms driving alpha-synuclein accumulation remain incompletely understood.
• Protease inhibitors like leupeptin can induce aging- and neurodegeneration-like changes in the brain.

Purpose of the Study:

• To investigate the in vivo effects of leupeptin administration on alpha-synuclein accumulation in a non-transgenic rodent model.
• To explore the potential role of impaired alpha-synuclein metabolism in its pathological aggregation.

Main Methods:

• Leupeptin was administered intracerebroventricularly into rat brains using an infusion pump.
• Immunohistochemistry and immunoelectron microscopy were employed to detect and localize alpha-synuclein.
• Confocal laser scanning microscopy was used to assess colocalization with ubiquitin.

Main Results:

• Leupeptin administration led to widespread appearance of alpha-synuclein-positive structures, primarily in neuronal processes (fimbria and alveus).
• Immunoelectron microscopy revealed alpha-synuclein accumulation within swollen axons and presynaptic terminals.
• Rare colocalization of alpha-synuclein with ubiquitin was observed.

Conclusions:

• This study provides the first evidence of experimentally induced in vivo alpha-synuclein accumulation in a non-transgenic rodent model using a protease inhibitor.
• The findings suggest that impaired alpha-synuclein metabolism, potentially involving lysosomal or ubiquitin-independent proteasomal pathways, can induce its local accumulation.
• This model offers insights into the early pathological events relevant to synucleinopathies.