The role of recombinant human laminin-111 in adhesion-signaling and glycosylation in laminin-⍺2 deficient muscle

LAMA2-related congenital muscular dystrophy (LAMA2-CMD) is a rare and severe neuromuscular disease characterized by progressive muscular degeneration. LAMA2-CMD is caused by mutations in LAMA2 which encodes for the laminin-α2 protein. Loss of laminin-α2 results in the absence of laminin-211/221, an extracellular matrix protein essential for anchoring skeletal muscle cells to the basal lamina. LAMA2-CMD patients experience profound muscle weakness from birth, demyelinating neuropathy, and muscle atrophy starting from a very young age. Currently there is no effective treatment nor cure, therefore there is an urgent unmet medical need to develop therapeutics for LAMA2-CMD. Spatial proteomics analysis of LAMA2-CMD patient biopsies revealed altered biological processes including protein aggregation, oxidative stress, and dysregulated glycolysis. In the LAMA2-CMD mouse model, the dyW, spatial proteomics showed similar altered proteins and dysregulated pathways to LAMA2-CMD patients. Including downregulation of MAPK and Akt signaling. After treatment with recombinant human laminin-111 (rhLAM-111), the differentially expressed proteins were restored to wild-type levels. Immunofluorescence also showed that rhLAM-111 could restore altered localization of the laminin adhesion complexes to the sarcolemma and led us to explore the glycan composition of the dyW and other dystrophic mouse models utilizing different types of lectins. These results suggest that laminin-deficient muscle experiences dysfunctional Golgi complex organization influenced by integrin-α7 binding. Altogether, these findings highlight novel mechanistic insights into laminin's role in regulating many integral biological pathways and the therapeutic potential of rhLAM-111 for mitigating disease progression in LAMA2-CMD.

Level thesis:degree_level

Doctorate Degree

Year dc:date.issued

2025

Author dc:creator

• Hermann, Hailey Jean

Advisor dc:contributor.advisor

• Burkin, Dean J

Committee members dc:contributor.committeemember

• Burkin, Heather R
• Baker, Josh E
• Leblanc, Normand
• Kidd, Thomas

• integrin-α7
• LAMA2-CMD
• laminin-111
• laminin-α2
• muscular dystrophy
• spatial-omics

Language dc:language.iso

en_US, English

Repository record dc:identifier.uri

https://scholarwolf.unr.edu/handle/11714/11477

OAI identifier oai:identifier

oai:scholarwolf.unr.edu:11714/11477