Bergmann glia processes are swollen and disorganized in people with SCA7.
Like crime scene detectives, researchers are investigating potential suspects and weapons involved in neurodegeneration. Murder, not suicide, kills cerebellar Purkinje cells in spinal cerebellar ataxia type 7 (SCA7), according to Custer et al. They report that mutant Bergmann glia can cause the death of wild-type Purkinje cells in a recent article in Nature Neuroscience.
SCA7 is a neurological disorder caused by polyglutamine expansion of the transcription factor ataxin-7. In a previous study, the authors generated transgenic mice expressing polyglutamine-expanded ataxin-7 under the control of the mouse prion protein promoter. Resulting transgenic mice expressed polyglutamine-expanded ataxin-7 throughout the cerebellum, but not in Purkinje cells, in which the prion protein promoter does not drive expression. The transgenic mice had uncoordinated muscle movement (ataxia) and Purkinje cell loss.
Where does polyglutamine-expanded ataxin-7 act to mediate Purkinje cell death? Bergmann glia cell bodies lie near Purkinje cell bodies, and Bergmann glia processes wrap around Purkinje cell dendrites in the molecular layer of the cerebellum. People with SCA7 show swollen and disorganized Bergmann glia cell processes.
The authors generated transgenic mice with ataxin-7 expressed under the control of the Gfa2 promoter, which targets expression specifically to Bergmann glia. Different lines of transgenic mice were generated with wild-type or polyglutamine-expanded ataxin-7.
Transgenic mice behaved normally until approximately 12 months of age. When suspended by their tails, mice expressing wild-type ataxin-7 stretched their arms and legs, but 12 month-old mice expressing polyglutamine-expanded ataxin-7 showed limb-clasping behavior. These mice fell faster than did mice expressing wild-type ataxin-7 when placed on a rotating rod.
Mice with polyglutamine-expanded ataxin-7 had cerebellar abnormalities. Their Purkinje cell dendrites were atrophied, and Purkinje cells were occasionally oriented in the wrong direction. By 9 months of age, Purkinje cells had vacuoles and Bergmann glia were swollen in mice expressing polyglutamine-expanded ataxin-7.
Bergmann glia 'mop up' excess glutamate at synapses to protect Purkinje cells. RT-PCR showed reduced expression of Slc1a3, which encodes the glutamate transporter GLAST, in mice expressing polyglutamine-expanded relative to mice expressing wild-type ataxin-7. In Bergmann glia cultures, cerebellar slice cultures or cerebellar synaptosomes, glutamate uptake was reduced with polyglutamine-expanded relative to wild-type ataxin-7.
Compromised glutamate transport in Bergmann glia leaves neurons vulnerable to excitotoxic cell death. Granule cell neurons co-cultured with Bergmann glia from mice expressing polyglutamine-expanded ataxin-7 showed more glutamate-induced cell death than neurons in similar cultures from mice expressing wild-type ataxin-7.
Therefore, the authors concluded that polyglutamine expansion of ataxin-7 disrupts glutamate transport (perhaps by interfering with transcription of GLAST) in Bergmann glia, leaving Purkinje cells vulnerable to excitotoxic cell death. Polyglutamine-expanded huntingtin decreases expression of the glutamate transporter GLT-1 in cultured cells, suggesting that neurodegeneration associated with Huntington disease may occur through a similar mechanism. Together, these data indicate that at least a subset of polyglutamine expansion diseases cause neurodegeneration by increasing neuronal vulnerability to excitotoxicity.