Neuronal LAG3 facilitates pathogenic α-synuclein neuron-to-neuron propagation

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Lymphocyte activation gene 3 (LAG3) is implicated in the spread of pathological proteins in Parkinson's disease (PD).
• Alpha-synuclein (αSyn) preformed fibrils (PFFs) are key drivers of PD pathology.
• Understanding the role of neuronal LAG3 in αSyn propagation is crucial for developing effective PD therapies.

Purpose of the Study:

• To investigate the role of neuronal LAG3 in the binding, uptake, and propagation of αSyn PFFs.
• To determine if targeting neuronal LAG3 can mitigate PD-associated pathology and neurodegeneration.

Main Methods:

• Utilized neuronal LAG3 conditional knockout mice and human induced pluripotent stem cells-derived dopaminergic (DA) neurons.
• Performed electrophysiological recordings to assess neuronal activity.
• Administered an anti-human LAG3 antibody to human DA neurons treated with αSyn PFFs.

Main Results:

• Absence of neuronal LAG3 significantly reduced αSyn pathology, motor dysfunction, and neurodegeneration in vivo.
• αSyn PFFs induced neuronal hyperactivity in wild-type neurons, an effect resisted by LAG3-deficient neurons.
• Anti-human LAG3 antibody treatment inhibited αSyn PFF binding and uptake in human DA neurons.

Conclusions:

• Neuronal LAG3 is essential for mediating αSyn propagation and associated pathological disruptions in Parkinson's disease.
• Targeting LAG3 presents a promising therapeutic strategy for PD and other alpha-synucleinopathies.
• LAG3 blockade effectively prevents αSyn pathology spread and neurotoxicity.