ALS-linked protein disulfide isomerase variants cause motor dysfunction.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Disturbed endoplasmic reticulum (ER) proteostasis is implicated in amyotrophic lateral sclerosis (ALS).
• Protein disulfide isomerases (PDIs) are ER foldases with potential roles as ALS biomarkers and neuroprotective factors.
• Functional studies on the impact of PDI mutations in ALS pathogenesis are lacking.

Purpose of the Study:

• To functionally characterize ALS-linked mutations in PDIA1 and PDIA3/ERp57.
• To investigate the impact of these PDI variants on motor neuron function and connectivity.
• To elucidate the molecular mechanisms underlying PDI mutant pathogenicity in ALS.

Main Methods:

• Phenotypic screening in zebrafish models.
• Motoneuron cell culture studies assessing dendritic outgrowth.
• Cellular and biochemical analyses of PDI mutant function.
• In vivo studies targeting ERp57 in the mouse nervous system.

Main Results:

• Expression of ALS-linked PDI variants in zebrafish induced motor defects and disrupted motoneuron connectivity.
• Mutant PDIs impaired dendritic outgrowth in motoneuron cell cultures.
• Distinct molecular defects were identified for different PDI mutants.
• Targeting ERp57 in the mouse nervous system caused severe motor dysfunction and loss of neuromuscular synapses.

Conclusions:

• ER proteostasis imbalance is a significant risk factor contributing to the initial stages of ALS.
• ALS-linked PDI mutations directly impact motor neuron structure and function.
• ERp57 dysfunction in the nervous system leads to motor deficits and synaptic loss, underscoring its role in ALS pathogenesis.