GPNMB enables lysosomal adaptation required for myelin clearance and nerve regeneration after peripheral nerve injury
- 1Diseases of Aging and Regenerative Medicines, Biomedical Research, Novartis, Basel, Switzerland
Abstract
Recovery from peripheral nerve injury involves coordinated axonal and immune repair programs that promote tissue regeneration. However, the mechanisms regulating immune-mediated repair remain incompletely understood. Here, we demonstrate that glycoprotein non-metastatic melanoma protein B (GPNMB) is a key regulator of repair processes following peripheral nerve injury. In a mouse sciatic nerve crush model, loss of Gpnmb impaired functional recovery after injury. MRI and histological analyses revealed persistent myelin debris accumulation, defective debris clearance, and impaired macrophage lysosomal function within injured nerves. Mechanistic studies showed that GPNMB-deficient human iPSC-derived macrophages exhibited impaired lysosomal adaptation, reduced lysosomal fitness, and defective processing of myelin-associated cargo, resulting in inefficient degradation of injury-associated material. These defects were accompanied by impaired acquisition of repair-associated cellular programs. Together, our findings identify GPNMB as a critical regulator of lysosome-dependent repair programs during nerve regeneration and demonstrate that efficient GPNMB-dependent myelin processing is required for functional recovery following peripheral nerve injury.
Related
- The WD40 domain of autophagy protein ATG-16.2 is required for lysosomal regulation and longevity in germline-less C. elegans
- Inflammatory proteostasis reprogramming creates a lysosomal bottleneck for microglial aggregate clearance
- Targeted lysosomal activation in bladder epithelium enhances clearance of intracellular uropathogenic Escherichia coli
- Syntaxin-1 and syntaxin binding protein 1-1 are required for planarian behavior and brain regeneration
- Lysosomal adaptation to extracellular acidity compromises CD8+ T cell cytotoxicity
BibTeX
@misc{alami2026gpnmb,
title = {{GPNMB enables lysosomal adaptation required for myelin clearance and nerve regeneration after peripheral nerve injury}},
author = {N. Ouali Alami and M. Panesar and M. Obrecht and T. Doll and I. Osinnii and G. Sansig and Z. Thiel and I. Claerr and D. Greenwood and C. Patino and L. Klein and D. Condeescu-Ivan and E. Giorgetti and C. Lambert and G. Kalamakis and V. Van Steenbergen and L. Hils and C. Manneville and M. Mueller and M. Nash and M. Labouesse and D. Shimshek and N. Beckmann and O. Dergai and M. Bidinosti},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.758439},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.758439v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - GPNMB enables lysosomal adaptation required for myelin clearance and nerve regeneration after peripheral nerve injury
AU - N. Ouali Alami
AU - M. Panesar
AU - M. Obrecht
AU - T. Doll
AU - I. Osinnii
AU - G. Sansig
AU - Z. Thiel
AU - I. Claerr
AU - D. Greenwood
AU - C. Patino
AU - L. Klein
AU - D. Condeescu-Ivan
AU - E. Giorgetti
AU - C. Lambert
AU - G. Kalamakis
AU - V. Van Steenbergen
AU - L. Hils
AU - C. Manneville
AU - M. Mueller
AU - M. Nash
AU - M. Labouesse
AU - D. Shimshek
AU - N. Beckmann
AU - O. Dergai
AU - M. Bidinosti
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.758439
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.758439v1
AB - Recovery from peripheral nerve injury involves coordinated axonal and immune repair programs that promote tissue regeneration. However, the mechanisms regulating immune-mediated repair remain incompletely understood. Here, we demonstrate that glycoprotein non-metastatic melanoma protein B (GPNMB) is a key regulator of repair processes following peripheral nerve injury. In a mouse sciatic nerve crush model, loss of Gpnmb impaired functional recovery after injury. MRI and histological analyses revealed persistent myelin debris accumulation, defective debris clearance, and impaired macrophage lysosomal function within injured nerves. Mechanistic studies showed that GPNMB-deficient human iPSC-derived macrophages exhibited impaired lysosomal adaptation, reduced lysosomal fitness, and defective processing of myelin-associated cargo, resulting in inefficient degradation of injury-associated material. These defects were accompanied by impaired acquisition of repair-associated cellular programs. Together, our findings identify GPNMB as a critical regulator of lysosome-dependent repair programs during nerve regeneration and demonstrate that efficient GPNMB-dependent myelin processing is required for functional recovery following peripheral nerve injury.
ER -