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Date of Graduation
Bachelor of Science (BS)
Department of Biology
Terrie K. Rife
Alzheimer's Disease (AD) and Parkinson's Disease (PD) are both progressive neurodegenerative disorders that affect millions of Americans and for which there are no cures. AD can significantly impair the ability to think, remember, communicate, and carry out daily activities, while PD can affect motor functions such as balance, coordination, and the ability to speak. Intracellular protein aggregation is a hallmark of both diseases, with AD being characterized by the build up of neurofibrillary tangles composed of misfolded tau protein and PD being characterized by Lewy bodies composed of alpha-synuclein. Both normal tau and alpha-synuclein can localize to the nucleus; however, their nuclear roles have not been fully elucidated. These proteins bind and stabilize alternative DNA structures, which form most readily at purine-pyrimidine repeats. The 1f promoter of the Nitric Oxide Synthase I (NOSI) gene, which is misregulated in both AD and PD, contains one such repeat. This NOSI repeat is polymorphic and has the sequence (TG)mTA(TG)n where m and n can vary from individual to individual. Genotyping shows that shorter dinucleotide polymorphisms are associated with AD and PD. Promoters with shorter repeats also have decreased transcriptional expression compared to promoters with larger repeats. Because tau and alpha-synuclein can bind such repeats, we hypothesize that tau and alpha-synuclein may modulate NOSI transcription through the (TG)nTA(TG)m repeat. Reporter genes directed by the NOSI 1f promoter with and without the (TG)nTA(TG)m repeat region were transfected into human neuroblastoma cells (SK-N-MC) and human cervical cancer cells (HeLa) that express varying levels of tau and alpha-synuclein. Promoters with the TG repeat directed approximately two-fold changes in reporter gene expression, while promoters without the TG repeat caused no change in expression. These findings suggest that tau and alpha-synuclein modulate NOSI expression through interaction with a dinucleotide polymorphism associated with disease development.
Weaver, Taelor A. and Deal, Alexandra L., "Modulation of nitric oxide synthase I transcription by Tau and Alpha-Synuclein and its relevance to Alzheimer's and Parkinson's diseases" (2016). Senior Honors Projects, 2010-current. 144.