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Peripheral neuropathy in a mouse model lacking GBA1 in Schwann cells
Loris Russo1, Ilaria Gregorio1, Samuele Negro2
1University of Padova, Department of Molecular Medicine, Padova, Via U. Bassi 58/b, Padova 35131, Italy.
Neurobiology of Disease
|August 3, 2026
Summary
Gaucher disease (GD) impairs peripheral nerve health by affecting Schwann cells (SCs). This study reveals that GBA1 deficiency in SCs disrupts myelin repair and nerve function, highlighting a novel role for GBA1 in nerve homeostasis.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Gaucher disease (GD) is a lysosomal storage disorder linked to peripheral neuropathic symptoms.
- The role of β-glucocerebrosidase (GBA1) in peripheral nerve myelination by Schwann cells (SCs) is not well understood.
- Investigating GBA1's function in SCs is crucial for understanding GD-related nerve complications.
Purpose of the Study:
- To investigate the involvement of peripheral myelination by Schwann cells (SCs) in Gaucher disease (GD).
- To determine the impact of β-glucocerebrosidase (GBA1) deficiency in SCs on peripheral nerve structure, function, and injury response.
- To elucidate the role of GBA1 in SC lysosomal function and its relevance to peripheral nerve homeostasis.
Main Methods:
- Generated a conditional knockout mouse model (Gba1f/f::cre) with GBA1 depletion in myelinating glia.
- Analyzed peripheral nerve morphology, myelin characteristics, and SC repair program activation (p75ntr, cJun).
- Assessed motor performance, neuromuscular junction morphology, and neuromuscular transmission.
- Investigated nerve injury response, including myelinophagy and autophagic flux, using in vivo and in vitro models with a GBA1 inhibitor (conduritol B epoxide).
Main Results:
- Gba1f/f::cre mice exhibited peripheral nerve hypomyelination, myelin infoldings, and activated SC repair programs.
- These mice showed reduced motor performance, altered neuromuscular junctions, and impaired neuromuscular transmission.
- While mice could recover from nerve injury, the initial steps of myelinophagy were impaired in GBA1-deficient SCs.
- Inhibition of GBA1 in vitro led to blocked autophagic flux, indicating impaired lysosomal function.
Conclusions:
- Decreased GBA1 activity in SCs leads to myelin and axonal defects due to impaired degradation and lipid accumulation.
- This sustains an SC repair program, contributing to neuropathic symptoms in Gaucher disease.
- GBA1 plays a critical role in maintaining SC lysosomal function, essential for peripheral nerve homeostasis and repair.
