Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction.

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Glycosphingolipids (GSLs), including brain-abundant gangliosides, are crucial bioactive membrane components.
• Defects in ganglioside metabolism lead to severe early-onset neurodegeneration, exemplified by Tay-Sachs and Sandhoff diseases due to GM2 accumulation.
• GM2 accumulation results from non-functional beta-hexosaminidase A.

Purpose of the Study:

• To investigate the cellular mechanisms underlying neuronal dysfunction in GM2-related gangliosidoses.
• To characterize the impact of GM2 storage on neuronal plasma membrane composition and function.
• To explore the role of lysosomal exocytosis in disease pathogenesis.

Main Methods:

• Development of i3Neuron-based disease models for gangliosidoses.
• Analysis of GM2 storage and endolysosomal dysfunction.
• Assessment of plasma membrane lipid and protein composition.
• Investigation of synaptic protein changes and lysosomal protein localization.

Main Results:

• i3Neuron models exhibited GM2 storage and severe endolysosomal dysfunction.
• Significant alterations in plasma membrane lipid and protein composition were observed.
• Lysosomal exocytosis was identified as a driver of lysosomal protein accumulation on the cell surface.
• Synaptic protein abundances were altered, affecting neuronal activity.
• Lysosomal protein enrichment at the plasma membrane was also observed in GM1 gangliosidosis models.

Conclusions:

• Gangliosidoses are characterized by severe plasma membrane disorders driven by lysosomal exocytosis.
• Lysosomal exocytosis contributes to altered plasma membrane proteome and neuronal dysfunction.
• These findings offer mechanistic insights into neurodegeneration and have implications for other lysosomal and neurodegenerative diseases.