Axonal transcriptome reveals upregulation of PLK1 as a protective mechanism in response to increased DNA damage in FUS P525L spinal motor neurons
Contact us if these videos are not relevant.
Contact us if these videos are not relevant.
View abstract on PubMed
Summary
This summary is machine-generated.Mutations in the FUSED IN SARCOMA (FUS) gene cause a form of amyotrophic lateral sclerosis (ALS). This study reveals unique axonal gene expression changes and identifies polo-like kinase 1 (PLK1) upregulation as a potential early event in FUS-ALS pathogenesis.
Area Of Science
- Neuroscience
- Genetics
- Molecular Biology
Background
- Mutations in the FUSED IN SARCOMA (FUS) gene are a common cause of genetic amyotrophic lateral sclerosis (ALS).
- Early FUS-ALS pathogenesis involves DNA damage response impairment and axonal degeneration, but the mechanisms linking these to selective motor neuron loss remain unclear.
- Understanding compartment-specific molecular changes in FUS-ALS is crucial for elucidating disease mechanisms.
Purpose Of The Study
- To investigate compartment-specific transcriptomic alterations in induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) with FUS mutations.
- To identify molecular pathways and potential therapeutic targets involved in the early pathogenesis of FUS-ALS.
- To explore the role of polo-like kinase 1 (PLK1) in FUS-ALS.
Main Methods
- Utilized microfluidic chambers for compartment-specific RNA sequencing of axonal and somatodendritic fractions from isogenic iPSC-derived MNs.
- Performed functional enrichment analysis on differentially expressed genes (DEGs) in axonal and somatic compartments.
- Investigated the effect of PLK1 inhibition on DNA damage and neuronal cell death in FUS-mutant MNs.
Main Results
- Demonstrated distinct axonal and somatic transcriptomes, with axons exhibiting fewer transcripts and enrichment in RNA metabolism and DNA damage pathways.
- Identified significant upregulation of cell cycle-associated genes, including PLK1, in FUS P525L mutant MNs.
- Showed that PLK1 inhibition exacerbated DNA damage and neuronal cell death in FUS-mutant MNs, suggesting a complex role in disease pathogenesis.
Conclusions
- Compartment-specific transcriptomics in human FUS-ALS MNs reveals unique axonal molecular profiles.
- Upregulation of PLK1 may be an early pathogenic event in FUS-ALS, potentially modulating DNA damage response and neuronal survival.
- These findings offer insights into the molecular mechanisms underlying FUS-ALS and suggest PLK1 as a potential therapeutic target.
Contact us if these videos are not relevant.
Contact us if these videos are not relevant.
Related Concept Videos
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Three of the best-understood negative regulators are p53, p21, and retinoblastoma protein (Rb). The regulatory roles of each of these proteins were discovered after faulty copies were found in cells with uncontrolled replication (i.e.,...
Plakins are large proteins with binding domains for microtubules, microfilaments, intermediate filaments, and membrane-associated protein complexes at cell junctions. Plakin functions are evolutionarily conserved and are primarily involved in organizing the different components of the cytoskeleton by crosslinking them to each other and connecting them to the cell-matrix and cell adhesion complexes. They are also known to interact with signal transducers, serve as scaffolds for signaling...