hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction
Department of Neurobiology; Budnik Lab
Animals; Animals, Genetically Modified; Carrier Proteins; Drosophila Proteins; Drosophila melanogaster; Female; Humans; Male; Membrane Proteins; Motor Neuron Disease; Neuromuscular Junction; Vesicular Transport Proteins
Neuroscience and Neurobiology
Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by selective death of motor neurons leading to spasticity, muscle wasting and paralysis. Human VAMP-associated protein B (hVAPB) is the causative gene of a clinically diverse group of MNDs including amyotrophic lateral sclerosis (ALS), atypical ALS and late-onset spinal muscular atrophy. The pathogenic mutation is inherited in a dominant manner. Drosophila VAMP-associated protein of 33 kDa A (DVAP-33A) is the structural homologue of hVAPB and regulates synaptic remodeling by affecting the size and number of boutons at neuromuscular junctions. Associated with these structural alterations are compensatory changes in the physiology and ultrastructure of synapses, which maintain evoked responses within normal boundaries. DVAP-33A and hVAPB are functionally interchangeable and transgenic expression of mutant DVAP-33A in neurons recapitulates major hallmarks of the human diseases including locomotion defects, neuronal death and aggregate formation. Aggregate accumulation is accompanied by a depletion of the endogenous protein from its normal localization. These findings pinpoint to a possible role of hVAPB in synaptic homeostasis and emphasize the relevance of our fly model in elucidating the patho-physiology underlying motor neuron degeneration in humans.
DOI of Published Version
Hum Mol Genet. 2008 Jan 15;17(2):266-80. Epub 2007 Oct 18. Link to article on publisher's site
Human molecular genetics
Chai, Andrea; Withers, James; Koh, Young Ho; Parry, Katherine; Bao, Hong; Zhang, Bing; Budnik, Vivian; and Pennetta, Giuseppa, "hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction" (2008). Neurobiology Publications and Presentations. 39.