# Exploring TMEM106B in Neurodegeneration: Protein Interaction and Fibril-induced Neurotoxicity

> **NIH NIH R36** · EMORY UNIVERSITY · 2024 · $52,082

## Abstract

PROJECT SUMMARY
The increasing aging population presents a heightened risk of neurodegenerative diseases.
Frontotemporal dementia (FTD) is one of these disorders and is the most common dementia in those under 60,
results from genetic mutations, particularly GGGGCC(G4C2) hexanucleotide repeat expansions in the
C9orf72 gene. These mutations, normally occurring 2-30 times in healthy individuals, can extend to hundreds
or thousands in C9orf72-related FTD and Amyotrophic Lateral Sclerosis (ALS) patients. TMEM106B is another
gene that is linked with neurodegeneration and particularly FTD and codes for a transmembrane protein
localized to the lysosome. Genome Wide Association Studies have shown single nucleotide polymorphisms
(SNPs) within the TMEM106B gene confer risk for various neurodegenerative disorders. It has been
shown that TMEM106B asks as a genetic modifier for C9orf72-related FTD. This dissertation proposal
delves into the complex interaction between TMEM106B and C9orf72 by examining the interplay between
TMEM106B and GA, a dipeptide repeat (DPR) proteins produced by C9orf72 hexanucleotide repeat
expansions. My preliminary data shows increased C-terminal cleavage of TMEM106B when co-expressed
with GA. Thus, I hypothesize that GA interacts with TMEM106B through its perturbation of the
proteosome pathway which in turn perturbs the clearance of a TMEM106B C-terminal cleaved product
and subsequently leads to neurotoxicity. This proposal also intends to investigate the toxicity of
TMEM106B aggregate prone fibrils. These fibrils were found in patients with different
neurodegenerative disorder as well as aged individuals while absent in young disordered and control
individuals. Individuals with risk SNPs have higher burden of TMEM106B fibrils which suggests a central
role in aging and neurodegeneration. Preliminary data shows that TMEM106B overexpression leads to
neurotoxicity as well as subsequent mislocalization of nuclear RNA binding proteins (RBPs). Thus, I
will test the hypothesis that TMEM106B fibrils play an important role in neurodegeneration and
contribute to toxicity and disease pathogenesis through disruption of the NCT. The Specific Aims of
this project are to: 1) Determine the interaction of TMEM106B and C9orf72 repeat expansion; and 2)
Determine the toxicity of TMEM106B fibrils and the underlying molecular mechanisms. Successful
completion of the proposed Aims will provide insights into TMEM106B’s interaction with C9orf72
and TMEM106B fibril’s contribution to aging and disease.

## Key facts

- **NIH application ID:** 10952583
- **Project number:** 1R36AG088283-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** KEDAMAWIT TILAHUN
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $52,082
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10952583

## Citation

> US National Institutes of Health, RePORTER application 10952583, Exploring TMEM106B in Neurodegeneration: Protein Interaction and Fibril-induced Neurotoxicity (1R36AG088283-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10952583. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*