Claudio Hetz, full professor at the Institute of Biomedical Sciences, Faculty of Medicine at the University of Chile in Santiago, was awarded an MDA research grant totaling $217,500 over a period of three years. The funds will help support Hetz’ study of protein misfolding and mislocation in amyotrophic lateral sclerosis (ALS).

The primary mechanism underlying nerve cell (motor neuron) death in ALS remains unknown. One hypothesis suggests that alterations in protein folding functions in a cellular compartment called the endoplasmic reticulum (ER) determine the aggregation and neurotoxicity of ALS-linked mutant SOD1 protein.

Hetz and colleagues have preliminary data that shows specific ER folding mediators called foldases are involved in cellular protection both in models of ALS and in human sporadic ALS spinal cord samples.

The team has demonstrated that induction of ER stress in motor neurons triggers a dramatic misfolding of normal SOD1 protein, resembling recent observations described in sporadic ALS-affected tissue. The investigators uncovered components of the stress pathway that mediate the abnormal misfolding of SOD1 and identified three foldases that can cause normal SOD1 to misfold.

In his new work, Hetz aims to define the impact of specific foldases on motor neuron dysfunction, and assess the possible therapeutic benefits of manipulating them in ALS.

“Since protein folding stress is a common event observed in familial and sporadic cases, our research may open novel possibilities for disease intervention in the near future,” Hetz said.