# Molecular Phenotyping of Cortical Cell Types in ALS Related Neurodegeneration

> **NIH NIH R56** · ROCKEFELLER UNIVERSITY · 2022 · $423,750

## Abstract

SUMMARY
 The combined degeneration of both “lower” motor neurons in the brainstem and spinal cord and “upper”
motor neurons (UMNs) in the cerebral cortex is an important hallmark of ALS. Almost all cases of ALS are
eventually fatal, and the rapid progression of the disease makes it particularly terrible, with over 80% of
patients dying within five years of diagnosis. No cure exists for ALS and the only available treatments slow
disease progression by merely a few months. Therefore, a great need exists for more effective and specific
therapies that can stop or even reverse neurodegeneration. Innovation for such therapies will only arise from a
better understanding of the molecular mechanisms underlying the pathological process. Most genes linked to
ALS are ubiquitously expressed yet only specific populations of cells degenerate. Understanding why certain
cells are uniquely vulnerable and mapping cell type specific pathways that are dysregulated during disease are
crucial milestones for developing innovative therapies. This has posed a considerable challenge for the spinal
cord-projecting upper motor neurons (UMNs) since they are difficult to distinguish from other pyramidal cell
types and are therefore often overlooked in preclinical studies. Because of this, the basis for their selective
vulnerability to disease-causing mutations has remained a mystery.
 The proposed study aims to overcome this by building on recent work that identified two highly similar
yet molecularly distinct subpopulations of projection neurons in layer 5b of motor cortex, where UMNs reside.
These populations have overlapping projections to pons, but non-overlapping projections to the spinal cord or
thalamus. Examining these cells in preclinical models of ALS revealed that the corticospinal projecting neurons
(CSTNs) were vulnerable to degeneration, while the corticopontine-only population (CPN) did not degenerate.
The selective vulnerability of the CSTNs was likely due to dysregulation of mitochondrial function since a
dramatic upregulation of genes related to oxidative phosphorylation and mitophagy was observed at
symptomatic stages of disease. Aim 1 of this grant will employ an integrative multi-omics approach to address
whether differences in the properties of mitochondria between CSTNs and CPNs drive differential responses to
disease using a novel, viral-based strategy to isolate cell type specific mitochondria during disease progression
in two preclinical ALS models, SOD1G93A and FUSP525L. Aim 2 focuses on characterizing the cellular role of
identified candidate genes that are enriched in CSTNs, shown to localize to mitochondria, and have been
directly linked to clinical cases of ALS and other neurodegenerative disorders. To increase the translational
significance of this work, Aim 3 will leverage novel markers for CSTNs and CPNs for a detailed anatomical
analysis of postmortem tissue from ALS patients perform transcriptional profiling on cell type specific nuclei
isol...

## Key facts

- **NIH application ID:** 10592732
- **Project number:** 2R56NS091722-06A1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Eric F Schmidt
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,750
- **Award type:** 2
- **Project period:** 2016-05-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592732

## Citation

> US National Institutes of Health, RePORTER application 10592732, Molecular Phenotyping of Cortical Cell Types in ALS Related Neurodegeneration (2R56NS091722-06A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10592732. Licensed CC0.

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