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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.