Proteostasis network alteration in lysosomal storage disorders: Insights from the mouse model of Krabbe disease

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Krabbe disease, a genetic disorder, results from GALC gene mutations, leading to severe demyelination and cell death.
• The precise molecular mechanisms underlying Krabbe disease pathogenesis, particularly early cellular dysfunctions, remain incompletely understood.

Purpose of the Study:

• To investigate the molecular mechanisms of early-onset Krabbe disease using the twitcher mouse model.
• To identify potential therapeutic targets by examining protein homeostasis, endoplasmic reticulum stress, and cytoskeleton integrity.

Main Methods:

• Analysis of protein synthesis, degradation, and proteasomal clearance in the brains of 6-day-old twitcher mice.
• Assessment of endoplasmic reticulum stress markers and immunoproteasome function.
• Evaluation of cytoskeleton remodeling, specifically lamin meshwork integrity in oligodendrocytes.

Main Results:

• Twitcher mice exhibit impaired protein synthesis and degradation, with compromised proteasomal clearance and endoplasmic reticulum stress.
• An imbalance in immunoproteasome function was observed in the twitcher mouse brain.
• Evidence of cytoskeleton remodeling, including lamin meshwork disaggregation in oligodendrocytes, was found in early-stage Krabbe disease.

Conclusions:

• Early Krabbe disease involves significant disruptions in protein homeostasis and cellular stress pathways.
• Cytoskeleton abnormalities, particularly in oligodendrocytes, contribute to the disease's early pathogenesis.
• Identifying these molecular targets may lead to novel combination therapies for Krabbe disease.