Amyotrophic lateral sclerosis (ALS), which is also known as Lou Gehrig's disease and motor neurone disease (MND), is a debilitating disease that causes the death of both cortical and spinal motor neurons, resulting in a loss of control over voluntary muscle. There is currently no cure for ALS, and the origin of the disease is largely unknown. In previous studies, VAMP/synaptobrevin-associated proteins (VAPs) have been associated with ALS and spinal muscular atrophy (SMA): specifically, the N-terminal major sperm protein domain (MSPd), which serves as an extracellular signalling molecule and which is mutated in some forms of familial ALS. In this issue, Sung Min Han, Michael Miller and colleagues investigate the molecular framework and functional consequences of MSPd signalling in C. elegans, with implications for muscle and gonad development.

In the first study (p. 2175), the authors focus on the role of MSPd in muscle formation, based on the expression of VPR-1, the C. elegans homologue of human VAPB. The authors show that secreted MSPds promote the localisation of mitochondria within the body wall muscle during development, and that this is dependent on signalling events that involve the CLR-1 Lar-like phosphatase receptor. Using a targeted RNAi screen of known genes implicated in ALS and SMA, the authors identified survival of motor neuron 1 (SMN-1) as a crucial downstream mediator of MSPd and further showed that SMN-1 and ARX-2 are important for mitochondria localisation along the I-bands in body wall muscle.

In the second study (p. 2187), the authors turn their attention to the role of VPR-1 in gonad development, an area in which the role of VPR-1 remains largely unexplored. Taking a genetic approach, the authors show that vpr-1 null mutants are sterile upon hatching, a defect in gonadogenesis that can be rescued by the expression of MSPd from almost any tissue, except for the somatic gonad itself. The authors further demonstrate that, under normal conditions, gonad development depends on germline and neuronal expression of vpr-1 and specifically on cleaved MSPd, which circulates in the pseudocoelom and induces gonadogenesis non-cell-autonomously, much like a hormone.

Together, these two studies represent a major step forward in our understanding of the function of the vpr-1 gene in C. elegans, and also demonstrate the utility of this organism in elucidating disease mechanisms.