James Withers PhD

James Withers


Publications:
2010
  Algorithms for automatic neuron tracing in noisy 3D image stacks
Knowles-Barley, S, Phillipson, G, Teriakidis, A, Sterratt, D, Larkworthy, T, O'Leary, T, Down, MP, Hennig, M, Withers, JPJ & Hull, M 2010, 'Algorithms for automatic neuron tracing in noisy 3D image stacks' Neuroscience Day 2010, Edinubrgh, United Kingdom, 29/03/10 - 29/03/10, .
General Information
Organisations: Institute for Adaptive and Neural Computation .
Authors: Knowles-Barley, Seymour, Phillipson, Graeme, Teriakidis, Adrianna, Sterratt, David, Larkworthy, Thomas, O'Leary, Timothy, Down, Matthew P., Hennig, Matthias, Withers, James P. J. & Hull, Michael.
Publication Date: 2010
Publication Information
Category: Poster
Original Language: English
  Characterization of the Properties of a Novel Mutation in VAPB in Familial Amyotrophic Lateral Sclerosis
Chen, H-J, Anagnostou, G, Chai, A, Withers, J, Morris, A, Adhikaree, J, Pennetta, G & de Belleroche, JS 2010, 'Characterization of the Properties of a Novel Mutation in VAPB in Familial Amyotrophic Lateral Sclerosis' Journal of Biological Chemistry, vol 285, no. 51, pp. 40266-40281. DOI: 10.1074/jbc.M110.161398

Following the mutation screening of genes known to cause amyotrophic lateral sclerosis (ALS) in index cases from 107 familial ALS (FALS) kindred, a point mutation was identified in vesicle-associated membrane protein-associated protein B (VAPB), or VAMP-associated protein B, causing an amino acid change from threonine to isoleucine at codon 46 (T46I) in one FALS case but not in 257 controls. This is an important finding because it is only the second mutation identified in this gene that causes ALS. In order to investigate the pathogenic effects of this mutation, we have used a motor neuron cell line and tissue-specific expression of the mutant protein in Drosophila. We provide substantial evidence for the pathogenic effects of this mutation in abolishing the effect of wild type VAPB in the unfolded protein response, promoting ubiquitin aggregate formation, and activating neuronal cell death. We also report that expression of the mutant protein in the Drosophila motor system induces aggregate deposition, endoplasmic reticulum disorganization, and chaperone up-regulation both in neurons and in muscles. Our integrated analysis of the pathogenic effect of the T46I mutation and the previously identified P56S mutation indicate extensive commonalities in the disease mechanism for these two mutations. In summary, we show that this newly identified mutation in human FALS has a pathogenic effect, supporting and reinforcing the role of VAPB as a causative gene of ALS.


General Information
Organisations: Centre for Integrative Physiology.
Authors: Chen, Han-Jou, Anagnostou, Georgia, Chai, Andrea, Withers, James, Morris, Alex, Adhikaree, Jason, Pennetta, Giuseppa & de Belleroche, Jackie S..
Keywords: (, , . )
Number of pages: 16
Pages: 40266-40281
Publication Date: 17 Dec 2010
Publication Information
Category: Article
Journal: Journal of Biological Chemistry
Volume: 285
Issue number: 51
ISSN: 0021-9258
Original Language: English
DOIs: 10.1074/jbc.M110.161398
2008
  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
Chai, A, Withers, J, Koh, YH, Parry, K, Bao, H, Zhang, B, Budnik, V & Pennetta, G 2008, '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' Human Molecular Genetics, vol 17, no. 2, pp. 266-280. DOI: 10.1093/hmg/ddm303
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.
General Information
Organisations: Centre for Integrative Physiology.
Authors: Chai, Andrea, Withers, James, Koh, Young Ho, Parry, Katherine, Bao, Hong, Zhang, Bing, Budnik, Vivian & Pennetta, Giuseppa.
Keywords: (, , . )
Number of pages: 15
Pages: 266-280
Publication Date: 15 Jan 2008
Publication Information
Category: Article
Journal: Human Molecular Genetics
Volume: 17
Issue number: 2
ISSN: 0964-6906
Original Language: English
DOIs: 10.1093/hmg/ddm303

Projects:
Validated co-registration and segmentation of multi-modal MRI (PhD)