Author:

Abstract:

Amyotrophic Lateral Sclerosis (ALS) is a devastating disease which is ch aracterized by the selective neurodegeneration of motor neurons in the m otor cortex, brainstem and spinal cord which results in paralysis and de ath usually within three years of disease onset. Most cases are sporadic (SALS) whilst inherited or familial forms (FALS) account for only a sma ll percentage. Different disease causing mutated genes have been identif ied in FALS of which superoxide dismutase 1 (SOD1) has been most extensi vely studied. As in other complex diseases, genetic variation is thought to play a rol e in the pathogenesis of SALS. Probably it acts in concert with other ri sk factors as ageing and environmental influences, determining disease s usceptibility. Furthermore, genetic variation is also believed to be able to modify the disease course. Genetic association studies in hum ans as well as genetic and/or chemical screenings in animal models are b eing performed in order to identify the genetic component in ALS. We here describe a small animal model for ALS which will enable large sc ale genetic and chemical screening. Overexpression of mutant SOD1 induce d a motor neuron axonopathy in the zebrafish embryo. The phenotype is motor neuron specific, very stereotypic in appearance, and is easy t o score quantitatively and in sufficient numbers to allow high-powered s tatistics. Moreover, known modifying factors influenced the phenotype si milar as in rodent models for ALS. This model will enable large scale sc reening for modifying factors in motor neuron diseases, ALS in particula r. Two independent genetic studies identified Elongator Protein 3 (ELP3) to be involved in motor neurobiology. ELP3 is part of a larger complex, th e Elongator. Holo-Elongator is a six-subunit complex composed of two sub complexes: core-Elongator (ELP1, ELP2 and ELP3) and a smaller component (composed of ELP4, ELP5 and ELP6). The Elongator and ELP3 in particular have several functions in RNA processing. It is involved in histone acet ylation, RNA elongation, modification of tRNA wobble nucleosides and exo cytosis. In a human association study variants in ELP3 were shown to be associated with ALS. Additionally in human brain of individuals with gen otypes associated with protection for ALS, levels of ELP3 were significa ntly higher. A mutagenesis screen in Drosophila also suggested decrea sed levels of ELP3 to be associated with abnormal axonal projections. Kn ock down of ELP3 in zebrafish resulted in defects in axonal outgrowth. I nterestingly, overexpression of ELP3 rescued the motor neuronal axonopat hy induced by mutant SOD1. These findings suggest increasing ELP3 to be beneficial for (motor) neurons and reduction in ELP3 to be a risk factor for (motor) neuronal diseases. The exact mechanism of action needs to b e elucidated. Potentially ELP3 can acetylate yet unknown cytoplasmic sub strates or influences one or more mechanisms in RNA processing, thereby affecting motor neuronal function and survival. Finally, we identified a new mutation in TARDBP by sequencing this recen tly described gene involved in both FALS and SALS. In our cohort of FALS patients SOD1 mutations are responsible for 35% of all cases, whilst TA RDBP was only identified in a minority of FALS (3%) in this population.