University of Tasmania, Australia

This project is composed of 2 parts:

1. Characterising the progression of amyotrophic lateral sclerosis in a mouse model.
2. Investigating whether metallothionein–I/II or its synthetic derivatives can delay the progression of ALS

Amyotrophic lateral sclerosis (ALS) is increasingly regarded as a complex multifactorial disease involving dysregulation of cellular processes affecting both neurons and glial. Proposed pathogenic mechanisms include oxidative stress and inflammation although it is still not clear whether inflammation is a primary cause or a consequence of neurodegeneration. In order to better understand the cellular changes that contribute to behavioural deficits in ALS, we are currently characterising changes in spinal cord motor neurons and microglia in terms of putative pro- and anti-inflammatory markers such as inducible nitric oxide synthase and arginase from pre-symptomatic to end-stage in the SOD1G93A mice. The SOD1G93A transgenic mouse line is one of the most widely used animal models of ALS, with disease onset occurring at less than 100 days postnatal, followed by progressive motor deterioration. We are also correlating neuronal and glial changes with behavioural deficits and neurofilament changes in the spinal cord.

The second part of our project addresses the question of whether metallothionein-I/II (MT) or its synthetic derivatives can provide an improved outcome in the SOD1G93A mice. Preliminary results show that pre-symptomatic treatment with MT slightly delayed disease onset and increased survival, but did not greatly affect stride length. Post-symptomatic treatment with MT derivatives (emtin peptides) increased survival and slightly affected stride length. Emtins are probably more suited to treatment of ALS than MT because it is known to cross the blood-brain barrier. We are currently undertaking analyses to determine the effect of MT and emtins on motorneurons in the spinal cord.