A mechanism for SCA10 neurodegeneration due to intronic repeat expansion

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Title: A mechanism for SCA10 neurodegeneration due to intronic repeat expansion
Author: Misti Caudle White
Abstract: 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
URI: http : / /hdl .handle .net /2152 .3 /87
Date: 2006-03-26


A mechanism for SCA10 neurodegeneration due to intronic repeat expansion. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /87 .

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