An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease

Abstract

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.

Identification and Functional Analysis of Truncated Human Glutamic Acid Decarboxylase 65

“…Another indication of the involvement of truncated GAD65 in neurological diseases comes from immunological studies. Autoantibodies to GAD65 are found in a rare neurological disorder called stiff man syndrome (SMS) [27] and a neurodegenerative disease called Batten disease [7]. Stiffness of axial muscles and superimposed painful spasms are characteristic of SMS and are alleviated by benzodiazepines, a finding that is consistent with the hypothesis that SMS represents an impairment of GABAergic neurotransmission in the central nervous system.…”

A Knock-In Reporter Model of Batten Disease

“…In the Cln3 ⌬ex1-6 mouse, mast cell infiltration occurs in the optic nerve, indicating loss of blood-brain barrier (BBB) at this site (Sappington et al, 2003). Furthermore, autoantibodies to GAD65, an enzyme involved in synthesis of the neurotransmitter GABA, are found in the sera from Batten disease mouse models (Chattopadhyay et al, 2002) and JNCL patients . This may reflect loss of barrier integrity and consequent GAD65 exposure to the immune system.…”

The role of anti-glutamic acid decarboxylase autoantibodies in mood disorders

“…Short-term treatment of depression in patients with diabetes improves their dysphoria and other signs and symptoms of depression. [65] In Batten disease, a rare genetic neurodegenerative disorder characterized by severe mental impairment, Chattopadhyay et al [66] studied a mouse model reporting the presence of an autoantibody to GAD 65 . These authors hypothesized that an autoimmune response to GAD 65 may contribute to a preferential loss of GABAergic neurons associated with Batten disease.…”

“…These authors hypothesized that an autoimmune response to GAD 65 may contribute to a preferential loss of GABAergic neurons associated with Batten disease. [66] Several groups observed an increased prevalence of autoimmune disease and/or autoantibodies in patients with BD, including autoimmune thyroiditis and autoimmune atrophic gastritis. More specifically, Padmos et al [67] studied 239 patients with DSM-IV BD, 74 patients with DSM-IV schizophrenia, and 220 healthy control subjects for detection of GAD 65 , GAD 67 , and thyroperoxidase antibodies (TPOA), formerly reported to have an increased prevalence in patients with BD.…”