A First Look into X-Linked Dystonia Parkinsonism
By Connie Cai
I performed research at the Bragg lab at the Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP) at Massachusetts General Hospital, a program that researches XDP, an adult onset neurodegenerative disease that almost exclusively affects males who live on the Panay Island in the Philippines. The disease, which is incredibly rare and understudied, is known to produce abnormal twisting postures. Aside from the fact that it is caused by a mutation in the TAF1 gene, a gene on the X-chromosome that encodes for a versatile transcription initiation factor protein, little is known about how this disease is caused.1
Our goal was to further our understanding of XDP by investigating in which cellular pathways TAF1 is involved, as well as how the TAF1 gene is regulated. To accomplish the first task, we began by conducting pathway activation studies. We used drugs that were known to activate certain cellular pathways—such as DNA damage, stress on the endoplasmic reticulum (ER), and cellular inflammation. We then tracked the level of TAF1 expression in these activated pathways. By looking for elevated levels of TAF1, we could glean whether or not TAF1 was involved in these pathways.
There are many approaches to tracking gene expression; we chose to use a downstream luciferase gene (a gene that encodes for a bioluminescent protein whose luminescence we can measure). A downstream gene is a gene that is expressed whenever its ‘upstream’ gene—in this case our TAF1 gene—is expressed. The more TAF1 is expressed, the higher the luminescent signal.
Our preliminary data from these activation studies show that treatment with etopside, a drug that stimulates DNA damage, and treatment with thapsigargin, a drug that stimulates ER stress, induces mild increases in TAF1 expression. This suggests that TAF1 might be involved in these two pathways, and by association, that these two pathways might be responsible for the onset of XDP.
While an incredibly useful diagnostic tool, these activation studies only show which pathways might be involved, not how they are directly linked to the symptoms of XDP. To improve the precision of our results, as well as to better understand the regulation of TAF1 regulation, we are currently using two transcription factors—ATF3 and NFκB-p65—that interact with the TAF1 gene. By overexpressing these transcription factors, we hope to see elevation in TAF1 gene expression. While the data from this experiment are still pending, we hope they will corroborate the results of our pathway activation studies.
Our research represents a first foray into understanding the cellular interactions that dictate the expression and transcription of the TAF1 gene. Our data points us in a new direction of looking more deeply into DNA damage and ER stress and how they relate to TAF1 expression and ultimately, XDP. While our data suggests a direction forward, it isn’t entirely clear. Such is the nature of research, particularly research on such an unknown and under-studied disease. Regardless, every data point pushes us closer to finding a cure for this devastating disease.
References
I performed research at the Bragg lab at the Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP) at Massachusetts General Hospital, a program that researches XDP, an adult onset neurodegenerative disease that almost exclusively affects males who live on the Panay Island in the Philippines. The disease, which is incredibly rare and understudied, is known to produce abnormal twisting postures. Aside from the fact that it is caused by a mutation in the TAF1 gene, a gene on the X-chromosome that encodes for a versatile transcription initiation factor protein, little is known about how this disease is caused.1
Our goal was to further our understanding of XDP by investigating in which cellular pathways TAF1 is involved, as well as how the TAF1 gene is regulated. To accomplish the first task, we began by conducting pathway activation studies. We used drugs that were known to activate certain cellular pathways—such as DNA damage, stress on the endoplasmic reticulum (ER), and cellular inflammation. We then tracked the level of TAF1 expression in these activated pathways. By looking for elevated levels of TAF1, we could glean whether or not TAF1 was involved in these pathways.
There are many approaches to tracking gene expression; we chose to use a downstream luciferase gene (a gene that encodes for a bioluminescent protein whose luminescence we can measure). A downstream gene is a gene that is expressed whenever its ‘upstream’ gene—in this case our TAF1 gene—is expressed. The more TAF1 is expressed, the higher the luminescent signal.
Our preliminary data from these activation studies show that treatment with etopside, a drug that stimulates DNA damage, and treatment with thapsigargin, a drug that stimulates ER stress, induces mild increases in TAF1 expression. This suggests that TAF1 might be involved in these two pathways, and by association, that these two pathways might be responsible for the onset of XDP.
While an incredibly useful diagnostic tool, these activation studies only show which pathways might be involved, not how they are directly linked to the symptoms of XDP. To improve the precision of our results, as well as to better understand the regulation of TAF1 regulation, we are currently using two transcription factors—ATF3 and NFκB-p65—that interact with the TAF1 gene. By overexpressing these transcription factors, we hope to see elevation in TAF1 gene expression. While the data from this experiment are still pending, we hope they will corroborate the results of our pathway activation studies.
Our research represents a first foray into understanding the cellular interactions that dictate the expression and transcription of the TAF1 gene. Our data points us in a new direction of looking more deeply into DNA damage and ER stress and how they relate to TAF1 expression and ultimately, XDP. While our data suggests a direction forward, it isn’t entirely clear. Such is the nature of research, particularly research on such an unknown and under-studied disease. Regardless, every data point pushes us closer to finding a cure for this devastating disease.
References
- Bragg, Christopher et al. “Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1,” 2017.
