A mechanism for SCA10 neurodegeneration due to intronic repeat expansion



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Spinocerebellar ataxia type 10 (SCA10) is the second most prevalent ataxia in Mexico and Brazil. Phenotype of the disorder first occurs around the third to fourth decade, generally after procreation, resulting in a highly transmissible autosomal dominant disease. SCA10 begins as gait ataxia, but as the cerebellum degenerates, progresses to difficulties swallowing, loss of limb coordination, ocular abnormalities, and a basic inability to perform daily tasks. The disorder is due to an intronic repeat expansion, ATTCT, in the gene Ataxin 10. Ataxin 10 is a protein of unknown function. However, Ataxin 10 from SCA10 patient samples is known to be fully transcribed and properly spliced, resulting in a normal, but expanded transcript. The results presented here demonstrate that the AUUCU transcript is the toxic species in SCA10. A ubiquitous protein within the cell, heterogeneous nuclear ribonucleoprotein kinase (hnRNP K), important for basic cellular function, binds the AUUCU expansion in in vitro binding experiments as well as within cell culture and in the brain of SCA10 transgenic animals. The loss of function of hnRNP K is hypothesized to induce SCA10 phenotypes by resulting in the translocation of Protein Kinase C ä (PKCä) to mitochondria, where it is known to activate apoptosis. Both induction of this mechanism through endogenous expression of expanded repeat and inactivation of hnRNP K, as well as rescue of the mechanism via reduced levels of Ataxin 10 transcript and overexpression of hnRNP K, are utilized to validate the proposed SCA10 mechanism. The data presented in this dissertation provides a mechanism for possible therapeutic intervention into SCA10. Additionally, many similarities exist between SCA10 and other repeat expansion disorders such as myotonic dystrophy, the most common form of muscular dystrophy, other Spinocerebellar ataxias, Freidreich’s Ataxia, and Fragile-X mental retardation, the most commonly inherited genetic disease. The results presented here provide a mechanism that can be utilized in the listed disorders to further understand the mechanism for therapeutical intervention.\r\n\r\n



spinocerebellar ataxia type 10, SCA10, PKC delta, neurodegeneration, hnRNP K