The wobbler mouse, an ALS animal model

Abstract

This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking similarities to ALS. The cellular effects of the wobbler mutation, cellular transport defects, neurofilament aggregation, neuronal hyperexcitability and neuroinflammation closely resemble human ALS. Now, 57 years after the first report on the wobbler mouse we summarize the progress made in understanding the disease mechanism and testing various therapeutic approaches and discuss the relevance of these advances for human ALS. The identification of the causative mutation linking the wobbler mutation to a vesicle transport factor and the research focussed on the cellular basis and the therapeutic treatment of the wobbler motor neuron degeneration has shed new light on the molecular pathology of the disease and might contribute to the understanding the complexity of ALS.

Fig. 1

The wobbler phenotype is caused by to the partial loss of GARP function. a Wild type- (+/+), wobbler mouse (wr/wr) with motor deficits, and a transgenic rescued mouse (wr/wr–Vps54) with a wild-type Vps54 transgene compensating the motor defect (Schmitt-John et al. 2005). b Schematic drawing of the Vps54 gene and amino acid sequence of the C-terminus of Vps54 proteins from various species. (1) indicates the wobbler point mutation in exon 23 of Vps54 leading to a glutamine instead of a conserved leucine. c Function of the GARP complex (2) in tethering early and late endosome-derived vesicles (3) to the TGN 11. The GARP complex consisting of Vps51, Vps52, Vps53 and Vps54 interacts with Rab6 (6) and Arl1 (7) and mediates vSNARE (4)–tSNARE (5) mediated fusion of the vesicle and target membrane. d The GARP complex (2) functions in the retrograde vesicle transport. Endocytic vesicles reach early endosomes (8) then late endosomes (9) and further to lysosomes (10). Alternatively, early and late endosome-derived vesicles (3) can be retrogradely transported to the TGN (11), where the GARP complex (2) is localized. The wobbler mutation destabilizes Vps54 and thereby the whole GARP complex and thus leads to a partial loss of GARP function and impairments of the retrograde vesicle traffic

Fig. 2

Cellular effects of the wobbler mutation. The schematic drawing show a lower motor neuron connected to skeletal muscle cells and associated with interneurons and glial cells, such as astrocytes, microglial cells, oligodendrocytes and Schwann cells. The effects on the different cells, motor neuron degeneration muscle atrophy, astrogliosis, microgliosis and the loss of GABAergic interneurons are indicated. The effects of the dysfunction of cellular processes are given with numbers: (1) the formation of APP- and Rab7-positive vacuoles, (2) neurofilament aggregations, (3) impaired axonal transport, (4) further ubiquitin-positive protein aggregates and mitochondrial dysfunction (5)