A study titled “Oligonucleotide-based Therapy in BAC-Mouse Models of SCA14” by researchers at the University of Washington in Seattle was recognized with a Pioneer SCA (spinocerebellar ataxia) Translational Research Award for its potential to develop a future SCA therapy.
Spinocerebellar ataxia type 14 (SCA14) is a dominant ataxia that, unlike Friedreich’s ataxia, is not caused expansion of a DNA repeat sequence. The disease is characterized by slowly progressive cerebellar ataxia, dysarthria, and nystagmus (an involuntary, rapid and repetitive movement of the eyes). Additional symptoms may include cognitive impairment, tremor, and sensory loss. As with other ataxias, there is currently no treatment to prevent, stop, or slow the progression of SCA14.
Previously, researchers discovered that SCA14 is caused by mutations in the gene coding for the enzyme protein kinase C gamma (PKC gamma). Researchers engineered transgenic mouse lines carrying either the normal PKC gamma gene or one of two SCA14-associated mutated forms.
While in the cells carrying the normal PKC gamma, the protein is correctly localized in the central nervous system, and during development, those carrying one of the mutated forms of PKC gamma result in large aggregates in cerebellar Purkinje cells (neurons in vertebrate animals located in the cerebellar cortex of the brain). The second mutated form of PKC gamma causes Purkinje cells to develop abnormal dendrites (short branched extensions of a nerve cell, along which impulses received from other cells at synapses are transmitted to the cell body).
Mice carrying only one working copy of the mouse PKC gamma gene are normal in neurologic terms and exhibit no Purkinje cell abnormalities.
In some cancers where abnormal kinases also play a role in disease pathogenesis, treatments targeting these proteins show promising results. In inherited neurodegenerative diseases, therapies using short nucleotide sequences to target and correct or suppress the mutant gene are currently under investigation.
These results represent a first step for developing potential novel effective therapies for SCA14.