Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: Implications for human motor neuron disease
- Equal contributors
1 King's College London, Pharmaceutical Science Research Division, 150 Stamford Street, London SE1 9NH, UK
2 Department of Cell Biology, Bielefeld University, 33501 Bielefeld, Germany
3 Kings College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK
4 Molecular Biology Department, Aarhus University, 8000 Aarhus, Denmark
5 Department of Neurosurgery, University of Marburg, Baldingerstrasse, 35033 Marburg, Germany
BMC Neuroscience 2011, 12:24 doi:10.1186/1471-2202-12-24Published: 7 March 2011
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown but hypotheses about disease mechanisms include oxidative stress, defective axonal transport, mitochondrial dysfunction and disrupted RNA processing. Whereas familial ALS is well represented by transgenic mutant SOD1 mouse models, the mouse mutant wobbler (WR) develops progressive motor neuron degeneration due to a point mutation in the Vps54 gene, and provides an animal model for sporadic ALS. VPS54 protein as a component of a protein complex is involved in vesicular Golgi trafficking; impaired vesicle trafficking might also be mechanistic in the pathogenesis of human ALS.
In motor neurons of homozygous symptomatic WR mice, a massive number of endosomal vesicles significantly enlarged (up to 3 μm in diameter) were subjected to ultrastructural analysis and immunohistochemistry for the endosome-specific small GTPase protein Rab7 and for amyloid precursor protein (APP). Enlarged vesicles were neither detected in heterozygous WR nor in transgenic SOD1(G93A) mice; in WR motor neurons, numerous APP/Rab7-positive vesicles were observed which were mostly LC3-negative, suggesting they are not autophagosomes.
We conclude that endosomal APP/Rab7 staining reflects impaired vesicle trafficking in WR mouse motor neurons. Based on these findings human ALS tissues were analysed for APP in enlarged vesicles and were detected in spinal cord motor neurons in six out of fourteen sporadic ALS cases. These enlarged vesicles were not detected in any of the familial ALS cases. Thus our study provides the first evidence for wobbler-like aetiologies in human ALS and suggests that the genes encoding proteins involved in vesicle trafficking should be screened for pathogenic mutations.