Two C-terminal sequence variations determine differential neurotoxicity between human and mouse α-synuclein.

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Alpha-synuclein (aSyn) aggregation is a key factor in synucleinopathies like Parkinson's disease (PD).
• Mouse aSyn has a T53 residue mimicking the human PD mutation A53T, but lacks observed neuropathology in mice.
• This study investigates the neurotoxicity and biochemical properties of human, mouse, and chimeric aSyn variants.

Purpose of the Study:

• To compare the neurotoxicity of human A53T aSyn, mouse aSyn, and their human-mouse chimeric variants.
• To elucidate the biochemical mechanisms underlying differences in aSyn neurotoxicity.
• To identify potential therapeutic targets for synucleinopathies.

Main Methods:

• Neurotoxicity was assessed in primary midbrain cultures and rat models using aSyn-encoding viral vectors.
• Biochemical properties, including fibrillization rates, morphology, and membrane interactions, were analyzed.
• Statistical analyses included ANOVA and Kruskal-Wallis tests.

Main Results:

• Mouse aSyn exhibited lower neurotoxicity than human A53T aSyn in both cellular and in vivo models.
• Human-to-mouse substitutions D121G and N122S partially accounted for the reduced neurotoxicity of mouse aSyn.
• Human A53T and a chimeric variant showed increased membrane-induced aggregation and vesicle disruption.

Conclusions:

• Mouse aSyn is less neurotoxic due to C-terminal substitutions inhibiting membrane-induced aggregation and vesicle permeabilization.
• Membrane-induced self-assembly is crucial for aSyn neurotoxicity.
• Inhibiting C-terminal aggregation could be a therapeutic strategy for synucleinopathies.