The heterogeneous nature of the genetic causes of ataxias and related disorders severely impedes the advancement of specific cures. Since genetically classified ataxia subtypes are often indistinguishable by clinical diagnosis, common pathological pathways are likely at play, and understanding the shared underlying mechanisms is a crucial direction of research. We have identified a novel mechanism of combinatorial post-transcriptional regulation between two disparate genes implicated in ataxia, PUM1 and VLDLR, and propose to investigate its role in a mouse model. Both PUM1 and VLDLR mutations have been independently found to cause cerebellar ataxia. Preliminary data shows that PUM can regulate the VLDLR 3' UTR through co-regulation with miRNAs. Therefore, elucidating the mechanistic connections between these ataxia- related genes promises to provide a more coherent view of disease development, to pinpoint key targets for therapeutic intervention, and to suggest methods of their control. The conceptual innovation of the proposed work resides in investigating a novel paradigm of combinatorial post-transcriptional control between RBPs and miRNAs, and its dysregulation, in mediating cerebellar ataxia. Furthermore, the study is significant because it aims to uncover new mechanistic insight into the connections between very recently identified factors in the disease. Achieving the specific aims of this proposal will provide a solid foundation for further major proposals studying the mechanism of PUM1 / miRNA interaction on the VLDLR mRNA and the means of its modulation.

Public Health Relevance

Many of the genetic mutations that cause cerebellar ataxia manifest in nearly identical disease symptoms, implying that common pathological pathways and mechanisms are affected, and understanding these mechanisms is a crucial direction of research. We have identified a novel mechanism that links two disparate genes implicated in ataxia, PUM1 and VLDLR, and propose to investigate this connection in a mouse model. Elucidating the mechanistic connections between these ataxia-related genes promises to provide a more coherent view of disease development, to pinpoint key targets for therapeutic intervention, and to suggest methods of their control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS118390-01
Application #
10042417
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Miller, Daniel L
Project Start
2020-06-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2022-05-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Genetics
Type
Earth Sciences/Resources
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521