# Subcellular mito-nuclear balance and gene expression dynamics in Alzheimers's disease

> **NIH NIH R21** · HARVARD MEDICAL SCHOOL · 2024 · $466,125

## Abstract

Defects in mitochondrial function and subcellular trafficking along neuronal subcompartments are
hallmarks of genetic and idiopathic Alzheimer’s disease (AD). Neurons rely heavily on proper
mitochondrial function and localization, as mitochondria play a dual role: buffering calcium and also
providing the energy required for synaptic transmission and local translation. Mitochondria maintain
their own extrachromosomal genome and must coordinate gene expression programs with the nuclear
genome (mitonuclear coordination) to correctly assemble oxidative phosphorylation (OXPHOS)
complexes that make up the electron transport chain. This coordination is vital for proper cellular
function, as mitonuclear imbalance leads to orphan OXPHOS subunits that can overwhelm proteostasis
pathways. How mitonuclear balance is affected in AD and the collective effects of AD pathology in
subcellular transcriptome dynamics —from transcription to degradation and localization—, for both
nuclear- and mitochondrial-encoded transcripts are unknown. We hypothesize that neuronal
architecture predisposes mitochondria located distal to the soma to mitonuclear imbalance, making
them prone to malfunction in neurodegenerative disease states. Recently, we developed a technique
(subcellular TimeLapse-seq: STLseq) that simultaneously quantifies the kinetic rates of transcription,
nuclear export, ribosome association, and degradation for each transcript, a process we refer to as
RNA-flow. This method combines RNA metabolic labeling and subcellular fractionation with Bayesian
modeling and has been adapted to capture mitochondrial-encoded genes, enabling quantitative
analysis of mitochondrial transcriptome dynamics and of mitonuclear co-regulation. Here, we will
analyze RNA-flow dynamics in AD by adapting STL-seq to neurons harboring AD-related mutations,
combined with the isolation of soma and neuronal projections. The overall goal of this proposal is to
determine the effects of AD in subcellular transcriptome dynamics and in mitonuclear coordination in
the soma and neuronal projections. In Specific Aim 1, we will use STL-seq to analyze the subcellular
transcriptome dynamics in AD and identify key regulatory factors. In Specific Aim 2, we will determine
the soma and neurites translatome, the mitonuclear coordination differences in soma and neuronal
projections, and how AD influences mitonuclear balance. The expected outcome from this grant will be
an understanding of AD pathology at the transcriptome, the translatome, and the mitonuclear
coordination levels in the soma and neuronal projections. These results will positively impact our
understanding of mitochondrial gene regulation in healthy neurons and in AD, exposing putative new
areas for therapeutic intervention.

## Key facts

- **NIH application ID:** 11053956
- **Project number:** 1R21AG091645-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Lee Stirling Churchman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,125
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11053956

## Citation

> US National Institutes of Health, RePORTER application 11053956, Subcellular mito-nuclear balance and gene expression dynamics in Alzheimers's disease (1R21AG091645-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/11053956. Licensed CC0.

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