Paradigms for the identification of new genes in motor neuron degeneration

Abstract

It is estimated that between 10-20% of amyotrophic lateral sclerosis (ALS) is familial and these cases encompass recessive and dominant modes of inheritance. So far, mutations in three genes, superoxide dismutase 1 (SOD1), the p150 subunit of dynactin (DCTN1), and alsin have been shown to be directly causal for motor neuron degeneration in humans. However, clearly the disorder is genetically heterogeneous and other causal genes remain to be found that explain the vast majority of familial ALS cases. Human genetics can be problematical in that it is difficult to detect linkage in disorders in which multiple loci give similar phenotypes and where families are often small. In addition, the vertical collection of generations is often not possible with late onset disorders. An excellent genetic model of humans is provided by the mouse. We can use mouse models of neurodegeneration to find new genes in the human population. These models are not exact replicas of the human condition, but are the mouse equivalent and are incredibly valuable resources for highlighting genes and biochemical pathways disrupted in ALS and other diseases. In addition mouse models give us access to both control and affected tissues, at all stages of development and disease, thus greatly facilitating our understanding of pathogenesis. They also provide us with model systems for testing new therapies. Here we describe the approach taken to the characterization of new models of motor neuron disease and illustrate this with examples, including a recently characterized mouse model, Legs at odd angles (Loa).

Relay of retrograde synaptogenic signals through axonal transport of BMP receptors

“…Axonal transport is essential for neuronal function and survival (Goldstein, 2003;Hafezparast et al, 2003;Holzbaur, 2004). In Drosophila motoneurons the BMP pathway is activated at the synaptic terminal but ultimately results in regulation of transcription in the nucleus (Ball et al, 2010;Kim and Marqués, 2010), thus this signaling pathway is dependent on long-range signal propagation.…”

“…Blockages in axonal transport result in death of the neuron and, if widespread, nervous system disorders (Goldstein, 2003). Errors in retrograde transport have been shown to cause neuron degeneration in diseases such as motor neuron disease, amyotrophic lateral sclerosis, and spinal muscle atrophy (Hafezparast et al, 2003;Levy et al, 2006).…”

Dynamic Meta-Analysis as a Therapeutic Prediction Tool for Amyotrophic Lateral Sclerosis

“…The most recognized impairments and their measures include mutations to cargos (Meyer and Potter 1995;Wong, He et al 2000) and molecular motor cargo carriers (Hafezparast, Ahmad-Annuar et al 2003;Teuchert, Fischer et al 2006;Mitchell and Lee, 2009) that prevent the cargo from be appropriately bound to either dynein or kinesin. Other deficits include correlations to energetics, such as decreased mitochondrial transport or a decrease in overall transport due to a drop in mitochondrial potential (Ackerley, Grierson et al 2004).…”

Microtubule-based transport – basic mechanisms, traffic rules and role in neurological pathogenesis

“…Recent evidence suggests that the tail region of dynein, through its subunits or associated proteins, controls its own motor activity. In vitro studies found that the legs at odd angles (Loa) mutation F580Y in the tail of the cytoplasmic dynein heavy chain (Hafezparast et al, 2003) inhibits motor processivity (Ori-McKenney et al, 2010). In addition, dynein-associated protein NudE (NDE1) and Lis1 are involved in the interaction between the tail and motor domains of dynein (OriMcKenney et al, 2010;Zylkiewicz et al, 2011).…”