Role of sRNA Modifications in Alzheimer’s Disease

NeuroGenomics and Informatics Center (NGI)

NeuroGenomics and Informatics Center – Pilot Grant Program – May 2023 to April 2024

Deep molecular phenotyping analyses (genomic, transcriptomic, etc.) have revolutionized our understanding of the mechanisms underlying Alzheimer’s Disease (AD) risk. However, there are some molecular phenotypes with still small sample sizes, and others that remain to be investigated. Non-coding RNAs (ncRNAs) are RNA molecules that make up about 98-99% of the mammalian transcriptome. They actively interact with nucleic acids and other molecules to play a regulatory role in the balance of transcription and translation. Of all organs, the central nervous system has the highest abundance, specificity, and interactions of ncRNAs. There are several classes of ncRNAs based on their length, structure, and function. Among those, small RNA are in general understudied in the context of AD. On top of that, sRNAs not only need to be processed to be active, but they also suffer from post-translational modifications that will further affect their action mechanism. This project will generate data on small RNA modifications for the first time in the field using RNA from brains of Alzheimer’s Disease patients and controls, adding a new -omic layer for studies conducted at the NGI.

Resolution of Parkinson-associated loci and creation of predictive models using multi-omic data analyses

Michael J. Fox Foundation

Parkinson’s Pathway Molecular Data Analysis Program – June 2022 to November 2023

Genetic studies have allowed us to understand better the genetic risk of suffering from Parkinson’s Disease. However, for most of the findings we do not know the biological meaning or consequence that leads or contributes to the onset of the diseases. Statistics and Informatics tools combining genetic information with other biological layers (proteins and RNA) will help identify the biological consequence of the identified genetic regions and provide potential drug targets along with better diagnostic tools. In this proposal and in collaboration with Dr. Cruchaga and his team, we will combine genetic data with protein measurements in the first aim, and RNA (specifically those that have a circular form) with genetic data in the second one. By performing different association analyses, we will link genes with proteins and circular RNAs that will help resolve the biological meaning of genetic changes that we can modulate using drugs. Additionally, we will use this data along with state-of-the-art bioinformatic tools to develop diagnostic tools to aide in the early diagnostic of Parkinson’s Disease.

Small RNA Pathophysiology and Multi‐omic Interactions in Alzheimer Disease Brains

Knight Alzheimer’s Disease Research Center

Knight-ADRC Developmental Projects – June 2022 to May 2024

This proposal aims to perform a comprehensive study of differentially expressed sRNAs in the brains of the Knight-ADRC AD participants. We will investigate which sRNAs are differentially expressed in brains, associated with CDR, or to NFT Braak score. Then, we will combine the sRNA data with other molecular phenotypes from the same brains (genome, transcriptome, proteome, and metabolome) to understand how these omic layers regulate each other in the context of AD brains and generate new hypotheses.

Pathophisiology of miRNA in Alzheimer’s Disease

Bright Focus Foundation

Standard Award Program in Alzheimer’s Disease Research Grant – July 2021 to June 2024

Small RNAs are short molecules of RNA that regulate gene expression. MicroRNAs are the most known and studied type of small RNAs. However, other families of sRNAs exist and are, in fact, more abundant than Micro RNAs. In the context of Alzheimer’s disease, only micro RNAs have been investigated, especially for their potential as biomarkers. Even though many candidates have been proposed, only a few of them have been identified by more than one study. In consequence, the relationship between Alzheimer’s disease and small RNAs is mostly unknown. In this proposal, we will characterize the different populations of small RNAs in the brain, plasma, and cerebrospinal fluid of individuals with Alzheimer’s disease. Then we will investigate their biological role by i) identifying which small RNAs are different between cases and controls in each tissue (brain, plasma, and cerebrospinal fluid); ii) use small RNAs to generate tools that allow disease prediction, and iii) use cellular models to investigate the biological consequences of dysregulating the identified small RNAs.

Plasma Cell-Free RNA as Non-Invasive Biomarker for Parkinson’s Disease

Department of Defense (DoD)

Parkinson’s Research Program – September 2020 to August 2022

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. There is no cure available, and the tools to diagnose and follow-up the disease are limited. The commonalities across neurodegenerative diseases make very difficult the differential diagnosis between Alzheimer disease, PD, Lewy body dementia among many others. In this proposal, we aim to create a tool that allows to differentially diagnose PD using an innovative approach. We propose to apply cell-free plasma RNA sequencing and state-of-the-art bioinformatics techniques to diagnose PD.

Plasma Cell-Free RNA as Non-Invasive Biomarker for Neurodegeneration

National Institute of Health (NIH)

K99/R00 Career Development Award – February 2020 to January 2025

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Pathological changes in the brain can be observed at least 15 years before clinical symptoms (preclinical stage). An early and accurate diagnosis tool could save $7.9 trillion in medical and care costs. Moreover, an effective therapeutic strategy could improve the clinical outcome if delivered early. There is a clear need to develop cost-effective and non-invasive biomarkers for AD that can be used to identify individuals before symptoms emerge and patients at early-symptomatic stages of the disease. These novel biomarkers could be also leveraged to monitor disease progression and responses to therapies. Cell-free nucleic acid diagnostic tests have revolutionized prenatal screening, and cancer research, diagnosis, and treatment. Furthermore, specific transcripts ascertained from cell-free RNA have been evaluated as biomarkers for AD, but so far, no high throughput approach has been attempted. The goal of this proposal is to use high throughput sequencing of cell-free nucleic acids from plasma to construct a prediction model for neurodegenerative diseases.

Plasma Cell-Free RNA as Alzheimer’s Disease Non-Invasive Biomarker

Alzheimer’s Drug Discovery Foundation (ADDF)

Diagnostics Accelerator Initiative – November 2019 to October 2022

This project measures gene products in the blood (called cell-free ribonucleic acid (cfRNA)) associated with Alzheimer’s disease. This type of test has revolutionized prenatal screening and cancer prognosis. A set of 25 gene products identified from a small number of Alzheimer’s patients will be assessed in a larger, well-characterized population to create, optimize, and evaluate a predictive disease model. This research will enable the generation of a novel, non-invasive test that can predict disease onset. This in turn will help with the correct diagnosis, appropriate clinical trial design for intervention, and disease monitoring.