Elucidating the pathological mechanisms of a repeat expansion neurodegenerative disease

ALS/FTD;C9orf72;Biochemistry

Chakravarty, Tushar

Johns Hopkins University

关键词: ALS/FTD;    C9orf72;    Biochemistry;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/59130/CHAKRAVARTY-THESIS-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

ALS/FTD are related progressive neurodegenerative genetic diseases that have been recently linked by a hexanucleotide repeat expansion of (GGGGCC)n in the gene of C90rf72. Post-mortem brain samples reveal distinct RNA foci in the nucleus and cytoplasm of affected neurons in patients harboring these tandem-repeats. To this end, the body of work described herein tests the hypothesis that transcription initiation occurs at the repeats. A system of plasmids was constructed to study this phenomenon. In addition, a DNA pulldown using single stranded DNA substrates that form secondary structures indicates that the heterogeneous nuclear ribonucleoprotein K (hnRNPK) binds to the antisense hairpin forming DNA. Knockdown of hnRNPK in HEK293T cells transfected with the repeat containing plasmid demonstrates that hnRNPK might play a role in modulating C9 gene expression. These results provide preliminary evidence that could extend our understanding of the mechanistic details involved in the C9orf72 repeat expansion disease.