Genetic modeling of degenerative diseases and mechanisms of neuronal regeneration in the zebrafish cerebellum.

The cerebellum is a highly conserved brain compartment of vertebrates. Genetic diseases of the human cerebellum often lead to degeneration of the principal neuron, the Purkinje cell, resulting in locomotive deficits and socio-emotional impairments. Due to its relatively simple but highly conserved neuroanatomy and circuitry, these human diseases can be modeled well in vertebrates amenable for genetic manipulation. In the recent years, cerebellar research in zebrafish has contributed to understanding cerebellum development and function, since zebrafish larvae are not only molecularly tractable, but also accessible for high resolution in vivo imaging due to the transparency of the larvae and the ease of access to the zebrafish cerebellar cortex for microscopy approaches. Therefore, zebrafish is increasingly used for genetic modeling of human cerebellar neurodegenerative diseases and in particular of different types of Spinocerebellar Ataxias (SCAs). These models are well suited to address the underlying pathogenic mechanisms by means of in vivo cell biological studies. Furthermore, accompanying circuitry characterizations, physiological studies and behavioral analysis allow for unraveling molecular, structural and functional relationships. Moreover, unlike in mammals, zebrafish possess an astonishing ability to regenerate neuronal populations and their functional circuitry in the central nervous system including the cerebellum. Understanding the cellular and molecular processes of these regenerative processes could well serve to counteract acute and chronic loss of neurons in humans. Based on the high evolutionary conservation of the cerebellum these regeneration studies in zebrafish promise to open therapeutic avenues for counteracting cerebellar neuronal degeneration. The current review aims to provide an overview over currently existing genetic models of human cerebellar neurodegenerative diseases in zebrafish as well as neuroregeneration studies using the zebrafish cerebellum. Due to this solid foundation in cerebellar disease modeling and neuronal regeneration analysis, the zebrafish promises to become a popular model organism for both unraveling pathogenic mechanisms of human cerebellar diseases and providing entry points for therapeutic neuronal regeneration approaches.