Abstract
BackgroundSpinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1.ResultsSymptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells.ConclusionsThese data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel “cerebellum-specific”, effective, and safe symptomatic drugs for the treatment of SCA1 in humans.
Highlights
Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells
Systemic administration of a selective mGlu1 receptor positive allosteric modulator (PAM) to SCA1 mutant mice, causes long-lasting improvements in motor symptoms associated with adaptive changes in cerebellar neuroplasticity
Labeling was highly specific because the band disappeared in the cerebellum of mGlu1-deficient crv4 mice [17]. mGlu1α mRNA and protein levels in the cerebellum did not differ between 4-week old presymptomatic SCA1 mice and their age-matched wild-type littermates (Figure 1A)
Summary
Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. Spinocerebellar ataxia type-1 (SCA1) is an inherited neurological disease caused by expansion of an unstable CAG repeat in the ataxin-1 (ATXN1) gene, which leads to progressive degeneration of Purkinje cells in the cerebellar cortex. A current theory on the pathogenesis of SCA1 is that polyglutamine expansion disrupts the physiological interaction between ATXN1 and nuclear proteins regulating gene transcription and RNA processing, such as Capicua, retinoic acid orphan receptor-α (RORα), and RBM17 [4]. None of these mechanisms can be targeted by pharmacological interventions, and there is currently no treatment for SCA1 and other types of spinocerebellar ataxia
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