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The Journal of Neuroscience, January 28, 2009, 29(4):951-963; doi:10.1523/JNEUROSCI.2582-08.2009
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Neurobiology of Disease
The Drosophila BEACH Family Protein, Blue Cheese, Links Lysosomal Axon Transport with Motor Neuron Degeneration
Angeline Lim1 andRachel Kraut2 1Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064, and 2Institute of Bioengineering and Nanotechnology, Agency for Science, Technology, and Research, Singapore 138669
Correspondence should be addressed to Rachel Kraut, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 639798. Email: rskraut{at}ntu.edu.sg
Impaired axon transport is one of the earliest pathological manifestations of several neurodegenerative diseases, and mutations in motor proteins can exacerbate or cause degeneration (Williamson and Cleveland, 1999; Gunawardena and Goldstein, 2004; Stokin and Goldstein, 2006). Compromised function in lysosomes and other degradative organelles that intersect with the lysosomal pathway are also strongly implicated in neurodegenerative disease pathology (Nixon and Cataldo, 2006; Rubinsztein, 2006). However, any functional link between these two phenomena has not as yet been recognized. Drosophila mutants in blue cheese (bchs) undergo progressive brain degeneration as adults and have shortened life span (Finley et al., 2003), but the cellular function of Bchs and the cause of degeneration have not been identified. A role in lysosomal trafficking is suggested by the homology of Bchs with the vesicle trafficking-associated BEACH (Beige and Chediak–Higashi) domain protein family (Wang et al., 2002; De Lozanne, 2003) and by its genetic interaction with a lysosomal transport pathway (Simonsen et al., 2007). Here, we describe the degeneration of a population of identified larval motor neurons in bchs mutants. We present evidence that Bchs is primarily lysosomal in those motor neurons in wild type and, using live fluorescence imaging of individual motor neurons in intact larvae, show that lysosomal vesicles fail to be transported toward motor neuron termini in bchs mutant and Bchs-overexpressing larvae. We suggest therefore that anterograde transport of lysosomes toward synaptic termini is a key factor in preventing motor neuron degeneration and that Bchs reveals a functional link between the lysosomal degradative pathway and transport.
Key words: degeneration; lysosome; transport; motoneuron; motor neuron; Drosophila; neuron death
Received June 6, 2008; revised Nov. 12, 2008; accepted Dec. 7, 2008.
Correspondence should be addressed to Rachel Kraut, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 639798. Email: rskraut{at}ntu.edu.sg
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[Abstract] [Full Text] [PDF]
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