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From transcriptomic to protein level changes in TDP-43 and FUS loss-of-function cell models
Claudia Colombrita1, Elisa Onesto2, Emanuele Buratti3
1Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center - Università degli Studi di Milano, Milan 20122, Italy; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy.
TDP-43 and FUS RNA-binding proteins regulate distinct transcriptomic changes in neuronal cells. Their depletion impacts splicing and gene expression, affecting neuronal function and RNA metabolism, with implications for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- TDP-43 and FUS RNA-binding proteins (RBPs) are implicated in amyotrophic lateral sclerosis and frontotemporal dementia.
- Understanding their physiological RNA targets is crucial for elucidating disease mechanisms.
- Previous high-throughput screenings yielded complex, difficult-to-compare data due to varied experimental designs.
Purpose of the Study:
- To comparatively assess the effects of TDP-43 and FUS loss-of-function on the whole transcriptome.
- To utilize a consistent human neuronal cell model for direct comparison.
- To define the physiological RNA targets and biological functions of TDP-43 and FUS.
Main Methods:
- Utilized Affymetrix Exon Arrays to analyze whole transcriptome changes.
- Employed the same human neuronal SK-N-BE cell model for both TDP-43 and FUS depletion studies.
- Performed functional annotation analysis and extended analysis at the protein level.
Main Results:
- TDP-43 and FUS depletion induced largely distinct splicing and gene expression changes.
- Common pathways regulated include neuron differentiation and cytoskeleton organization.
- Specific genes involved in neuronal function (e.g., SEPT6, TNIK) and RNA metabolism (e.g., DICER, ELAVL3) were identified.
- Transcriptomic changes impacted protein isoform ratio and content, not always correlating directly with RNA data.
- Mutant TDP-43 retained splicing activity in ALS fibroblasts and cell lines, unlike a loss-of-function mechanism.
Conclusions:
- TDP-43 and FUS exhibit distinct roles in regulating gene expression and splicing in neurons.
- Findings contribute to defining the physiological functions of these RBPs.
- Highlights the importance of evaluating transcriptomic changes at the protein level in neuronal models.
- Provides insights into pathogenic mechanisms in neurodegenerative diseases involving TDP-43 and FUS.
