Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport

Abstract

Non-neuronal cells may be pivotal in neurodegenerative disease, but the mechanistic basis of this effect remains ill-defined. In the polyglutamine disease spinocerebellar ataxia type 7 (SCA7), Purkinje cells undergo non-cell-autonomous degeneration in transgenic mice. We considered the possibility that glial dysfunction leads to Purkinje cell degeneration, and generated mice that express ataxin-7 in Bergmann glia of the cerebellum with the Gfa2 promoter. Bergmann glia-specific expression of mutant ataxin-7 was sufficient to produce ataxia and neurodegeneration. Expression of the Bergmann glia-specific glutamate transporter GLAST was reduced in Gfa2-SCA7 mice and was associated with impaired glutamate transport in cultured Bergmann glia, cerebellar slices and cerebellar synaptosomes. Ultrastructural analysis of Purkinje cells revealed findings of dark cell degeneration consistent with excitotoxic injury. Our studies indicate that impairment of glutamate transport secondary to glial dysfunction contributes to SCA7 neurodegeneration, and suggest a similar role for glial dysfunction in other polyglutamine diseases and SCAs.

Are astrocytes executive cells within the central nervous system?

“…5) Regarding spinocerebellar ataxias, Garden et al 52 and, later on, Custer et al 53 produced mice expressing ataxin-7 only in Bergmann glia, which was sufficient to bring on ataxia and neuronal degeneration.…”

“…In amyotrophic lateral sclerosis (ALS), astrogliosis and microgliosis are hallmarks of the illness all along its course 53 . Other observations support the idea that an early primary astrocytic damage occurs in this disease 2 .…”

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

“…The role of neuron-glia interactions is also being investigated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Sheldon and Robinson, 2007). Moreover, glial dysfunction is likely to contribute to the pathogenesis of cerebellar ataxia in a mouse model of spinocerebellar ataxia type 7 (SCA7) (Custer et al, 2006).…”

“…The role of neuron-glia interactions is also being investigated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Sheldon and Robinson, 2007). Moreover, glial dysfunction is likely to contribute to the pathogenesis of cerebellar ataxia in a mouse model of spinocerebellar ataxia type 7 (SCA7) (Custer et al, 2006).Excitatory amino acids transporter 1 (EAAT1, also known as GLAST) is the major glutamate transporter in the cerebellum (Lehre and Danbolt, 1998). It is expressed strongly by astrocytes in the molecular layer of the cerebellum and is at highest density on Bergmann glia.…”

Les astrocytes dans la chorée de Huntington

“…Enfin, une co-culture avec des astrocytes qui expriment la protéine Huntingtine mutée protège de manière moins efficace les neurones du cortex cérébral ou du striatum soumis à des processus excitotoxiques liés au glutamate. Des effets délétères sur les cellules gliales ont également été observés dans d'autres maladies liées à la présence de longues chaînes polyglutaminées dans d'autres protéines : c'est le cas dans l'ataxie spino-cérébelleuse de type 3 (SCA3) dans un modèle chez la drosophile [20] ou, plus récemment, l'ataxie spino-cérébelleuse de type 7 (SCA7) dans des souris transgéniques [21]. Dans ce dernier article, les auteurs ont exprimé la protéine Ataxine 7 mutée sélective-ment dans la glie de Bergmann du cervelet et ont observé un déficit du transport du glutamate et une dégénérescence des neurones de Purkinje.…”