Neurodegenerative diseases, Amyotrophic Lateral Sclerosis

Research in the laboratory focuses on the study of the cellular and molecular events that lead to motor neuron death in Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig' s disease.

ALS is a typical neurodegenerative disease caused by degeneration and death of motor neurons in the spinal cord, brain stem and motor cortex. This leads to muscular atrophy. Death occurs 3 to 5 years from onset. Currently there is no cure for ALS.

The work we do in the laboratory focuses on one particular form of the disease: familial ALS caused by mutations in the gene encoding for the cytosolic copper-zinc superoxide dismutase (SOD1). We study the molecular mechanism(s) by which mutated SOD1 (mutSOD1) causes motor neuron degeneration. The ultimate goal is to identify potential therapeutic targets.

To this end, work in the laboratory develops in two components:

1. Basic research
2. Drug screening or translational research
   

Basic Research

Mutations in SOD1 cause motor neuron death through gain of toxic properties that are not fully delineated. This toxicity impairs multiple cellular functions. Mitochondrial abnormalities and activation of cell death genes are characteristic features of mutSOD1-mediated ALS. Our basic research program studies: a) the molecular switches that, upon mutation, convert SOD1 (normally a pro-survival protein) into a toxic molecule using in vitro biochemical approaches,
b) the pathological mechanisms governing mutSOD1-mediated cell death and mitochondrial dysfunction in neuronal cultures and transgenic animal models.

Drug Screening

What we learn from our basic research gets translated into the development of cell based assays to screen for therapeutics. The goal is to develop drugs to cure or ameliorate the disease.

We use different techniques from basic molecular biology to biochemistry and cell biology. We use cloning, protein electrophoresis, immunoblotting, immunofluorescence and immunoprecipitation techniques, in vitro affinity binding assays and subcellular fractionation to isolate organelles from the spinal cord of ALS mice.

As model systems we use neuronal cell cultures with mutSOD1 and transgenic ALS mice that express the human-mutated SOD1 gene. These mice develop and ALS-like disorder; we follow pathogenic molecular changes in the motor neurons of these mice as disease progresses.