New technology shows that many genes are transcribed (the first step in genetic expression) as multiple, different forms of RNA (molecules that play a role in genetic expression). These different forms may ultimately encode the same protein. Preliminary data show that a select alpha-synuclein transcript with a longer three prime untranslated region may play a role in Parkinson’s disease (PD) pathology. The three prime untranslated region (3’UTR) is a regulatory region of messenger RNA. This project aims to confirm the preliminary findings and examine the involvement of alpha-synuclein 3’UTR regulation in other disorders characterized by alpha-synuclein aggregation.
Using biosamples available through The Michael J. Fox Foundation, researchers will attempt to 1) confirm the increase in alpha-synuclein transcript with extended 3’UTR in PD patients’ brain 2) examine the specificity of such phenomenon through comparison to other neurodegenerative diseases 3) study the effect of common genetic variants associated with PD risk on alpha-synuclein transcript with extended 3’UTR 4) relate alpha-synuclein transcript with extended 3’UTR to alpha-synuclein protein accumulation.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The main deliverable would be the identification of a subset of alpha-synuclein transcript forms as major culprits in PD. Defining a selective association of the longer alpha-synuclein transcript with PD risk may allow for the development of therapies that impact the disease role of alpha-synuclein without attacking normal functions.
We expect to confirm the role of 3’UTR alpha-synuclein transcripts in human brain in Parkinson’s disease, both in patients and in individuals at higher risk of PD (due to genetic predisposition). We also expect to relate such findings to alpha-synuclein levels.
We have used next-generation sequencing (NGS) methods to query different forms of RNA present in human brain tissue that encode alpha-synuclein, a key player in Parkinson’s disease (PD). Many brain proteins such as alpha-synuclein are encoded by a variety of RNAs of different lengths, and we hypothesized that (i) some of these forms – especially longer ones - of alpha-synuclein RNA, may be enriched in PD brains, or brains at high risk for PD (due to genetic factors);and (ii) furthermore that longer forms of alpha-synuclein RNA may lead to altered production or localization of alpha-synuclein protein, which is a likely culprit in PD. To test this, we have generated a large dataset of gene expression and protein expression from human brain tissue. Furthermore, we assessed these brain tissues for genetic risk factors for PD. Our analyses of these large datasets are ongoing. These studies may identify very selective targets for future PD therapeutic development, as well as novel and specific biomarkers of PD.