Human Molecular Genetics, 2002, Vol. 11, No. 12 1421-1431
© 2002 Oxford University Press
An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease
1Center for Aging and Developmental Biology, 2Department of Pathology and Laboratory Medicine, 3Center for Functional Genomics, 4Department of Environmental Medicine and 5Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA and 6Department of Neuropathology, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK
Received January 29, 2002; Accepted April 10, 2002
Mutations in the CLN3 gene are responsible for the neurodegenerative disorder Batten disease; however, the molecular basis of this disease remains unknown. In studying a mouse model for Batten disease, we report the presence of an autoantibody to glutamic acid decarboxylase (GAD65) in cln3-knockout mice serum that associates with brain tissue but is not present in sera or brain of normal mice. The autoantibody to GAD65 has the ability to inhibit the activity of glutamic acid decarboxylase. Furthermore, brains from cln3-knockout mice have decreased activity of glutamic acid decarboxylase as a result of the inhibition of this enzyme by the autoantibody, resulting in brain samples from cln3-knockout mice having elevated levels of glutamate as compared with normal. This elevated glutamate in the brain of cln3-knockout mice co-localizes with presynaptic markers. The decreased activity of GAD65 and increased levels of glutamate may have a causative role in astrocytic hypertrophy evident in cln3-knockout mice, and in altered expression of genes involved in the synthesis and utilization of glutamate that underlie a shift from synthesis to utilization of glutamate. An autoantibody to GAD65 is also present in sera of 20 out of 20 individuals tested who have Batten disease. Postmortem tissue shows decreased reactivity to an anti-GAD65 antibody that may be due to loss of GAD65-positive neurons or due to the reactive epitope being blocked by the presence of the autoantibody. We propose that an autoimmune response to GAD65 may contribute to a preferential loss of GABAergic neurons associated with Batten disease.
* To whom correspondence should be addressed at: Center for Aging and Developmental Biology, Department of Biochemistry and Biophysics, Box 645, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, USA. Tel: +1 585 273 1514; Fax: +1 585 506 1972; Email: david_pearce{at}urmc.rochester.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Aberg, M. Talling, T. Harkonen, T. Lonnqvist, M. Knip, R. Alen, H. Rantala, and J. Tyynela INTERMITTENT PREDNISOLONE AND AUTOANTIBODIES TO GAD65 IN JUVENILE NEURONAL CEROID LIPOFUSCINOSIS Neurology, April 1, 2008; 70(14): 1218 - 1220. [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Eliason, C. S. Stein, Q. Mao, L. Tecedor, S.-L. Ding, D. M. Gaines, and B. L. Davidson A Knock-In Reporter Model of Batten Disease J. Neurosci., September 12, 2007; 27(37): 9826 - 9834. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Zhang, Y.-C. Lee, S.-J. Kim, M. S. Choi, P.-C. Tsai, A. Saha, H. Wei, Y. Xu, Y.-J. Xiao, P. Zhang, et al. Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration Hum. Mol. Genet., April 1, 2007; 16(7): 837 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-W. Chang, H. Choi, H.-J. Kim, D.-G. Jo, Y.-J. Jeon, J.-Y. Noh, W. J. Park, and Y.-K. Jung Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin Hum. Mol. Genet., February 1, 2007; 16(3): 317 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Pears, J. D. Cooper, H. M. Mitchison, R. J. Mortishire-Smith, D. A. Pearce, and J. L. Griffin High Resolution 1H NMR-based Metabolomics Indicates a Neurotransmitter Cycling Deficit in Cerebral Tissue from a Mouse Model of Batten Disease J. Biol. Chem., December 30, 2005; 280(52): 42508 - 42514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Neurology Arch. Dis. Child., April 1, 2005; 90(suppl_2): A46 - A47. [Full Text] [PDF]
|
|
|
|
|
|
D. Ramirez-Montealegre, S. Chattopadhyay, T. M. Curran, C. Wasserfall, L. Pritchard, D. Schatz, J. Petitto, D. Hopkins, J. -X. She, P. G. Rothberg, et al. Autoimmunity to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease Neurology, February 22, 2005; 64(4): 743 - 745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Pearce, M. Atkinson, and D. A. Tagle Glutamic acid decarboxylase autoimmunity in Batten disease and other disorders Neurology, December 14, 2004; 63(11): 2001 - 2005. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chattopadhyay, E. Kingsley, A. Serour, T. M. Curran, A. I. Brooks, and D. A. Pearce Altered Gene Expression in the Eye of a Mouse Model for Batten Disease Invest. Ophthalmol. Vis. Sci., September 1, 2004; 45(9): 2893 - 2905. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. G. Rothberg, D. Ramirez-Montealegre, S. D. Frazier, and D. A. Pearce Homogeneous Polymerase Chain Reaction Nucleobase Quenching Assay to Detect the 1-kbp Deletion in CLN3 That Causes Batten Disease J. Mol. Diagn., August 1, 2004; 6(3): 260 - 263. [Abstract] [Full Text]
|
|
|
|
|
|
R. M. Sappington, D. A. Pearce, and D. J. Calkins Optic Nerve Degeneration in a Murine Model of Juvenile Ceroid Lipofuscinosis Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 3725 - 3731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chattopadhyay, E. Kriscenski-Perry, D. A. Wenger, and D. A. Pearce An autoantibody to GAD65 in sera of patients with juvenile neuronal ceroid lipofuscinoses Neurology, December 10, 2002; 59(11): 1816 - 1817. [Full Text] [PDF]
|
|