Animal Models of Human Cerebellar Ataxias: a Cornerstone for the Therapies of the Twenty-First Century

Abstract

Cerebellar ataxias represent a group of disabling neurological disorders. Our understanding of the pathogenesis of cerebellar ataxias is continuously expanding. A considerable number of laboratory animals with neurological mutations have been reported and numerous relevant animal models mimicking the phenotype of cerebellar ataxias are becoming available. These models greatly help dissecting the numerous mechanisms of cerebellar dysfunction, a major step for the assessment of therapeutics targeting a given deleterious pathway and for the screening of old or newly synthesized chemical compounds. Nevertheless, differences between animal models and human disorders should not be overlooked and difficulties in terms of characterization should not be occulted. The identification of the mutations of many hereditary ataxias, the development of valuable animal models, and the recent identifications of the molecular mechanisms underlying cerebellar disorders represent a combination of key factors for the development of anti-ataxic innovative therapies. It is anticipated that the twenty-first century will be the century of effective therapies in the field of cerebellar ataxias. The animal models are a cornerstone to reach this goal.

The Moonwalker Mouse: New Insights into TRPC3 Function, Cerebellar Development, and Ataxia

“…A large number of mouse mutants exhibiting a cerebellar ataxia phenotype have been reported (reviewed in [6, 7]). Historically, the first ataxic mouse models that were intensively investigated were naturally occurring mutants, including the Lurcher (gain-of-function mutation in Grid2 ), staggerer ( Rora deletion), and Weaver mouse (gain-of-function mutation in Girk2 ).…”

Patterned Purkinje cell loss in the ataxic sticky mouse

“…Purkinje cell loss has been described during normal development and in numerous genetic, toxic, vascular, infectious and immune conditions in humans and other animals (reviewed in Dusart et al. , 2006; Manto & Marmolino, 2009; Sarna & Hawkes, 2003). Remarkably, Purkinje cell degeneration has commonly been found to be patterned, reflecting the underlying topography of the cerebellar cortex.…”

TGF-β1 Provides Neuroprotection via Inhibition of Microglial Activation in 3-Acetylpyridine-Induced Cerebellar Ataxia Model Rats

“…3-AP, known as methyl β-pyridyl ketone, is a metabolic antagonist utilized to decrease nicotinamide level of laboratory animals in research. Although a large number of laboratory animals with neurological mutations have been reported and numerous relevant animal models mimicking the phenotype of CAs are becoming available (Manto and Marmolino, 2009), the administration of 3-AP has still been suggested as a classic method to induce the CA animal model and provokes many characteristics similar to the typical features of CA in human (Janahmadi et al, 2009;Wecker et al, 2017). The application of 3-AP selectively lesions the neurons in the medial inferior olive, leading to a loss of climbing fibers innervating cerebellar Purkinje cells and a consequent ataxia manifested by alterations in both balance and gait (Rondi-Reig et al, 1997;Gasbarri et al, 2003;Wecker et al, 2013).…”