α-Synuclein-112 Impairs Synaptic Vesicle Recycling Consistent With Its Enhanced Membrane Binding Properties

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA), are linked to alpha-synuclein (α-syn) aggregation.
• While wild-type α-syn (α-syn-140) toxicity is known, the role of α-syn splice isoforms remains understudied.

Purpose of the Study:

• To investigate the synaptic effects of the α-synuclein-112 (α-syn-112) splice isoform.
• To elucidate the biochemical properties and in vivo synaptic impact of α-syn-112.

Main Methods:

• Investigated α-syn-112 binding to phospholipids using liposomes.
• Assessed α-syn-112 oligomerization on isolated synaptic membranes.
• Examined the effects of α-syn-112 on synaptic vesicle recycling in lamprey synapses.

Main Results:

• α-Syn-112 exhibited stronger binding to phospholipids than α-syn-140.
• α-Syn-112 readily formed dimers and trimers on synaptic membranes, unlike monomeric α-syn-140.
• α-Syn-112 robustly inhibited synaptic vesicle recycling, with effects intermediate between monomeric and dimeric α-syn-140.

Conclusions:

• α-Syn-112 possesses enhanced phospholipid binding and oligomerization capabilities.
• These properties contribute to impaired synaptic vesicle recycling, a potential mechanism in synucleinopathies.
• The study advances understanding of α-syn-112's role in neurodegenerative disease pathogenesis.