Predictors of conversion from major depressive disorder to bipolar disorder: A population-based PADRIS-PRESTO cohort study in Catalonia.

The TAR DNA-binding protein 43 (TDP-43), encoded by the gene, is a highly conserved DNA/RNA-binding protein implicated in RNA processing that includes RNA splicing, mRNA stability and trafficking. It is mainly located in the nucleus and is expressed in all cell types. TDP-43 aggregates, initially described in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have emerged as a component of multiple neurodegenerative conditions, including Alzheimer’s disease (AD). Pathological cytoplasmic inclusions, characterized by hyperphosphorylated and ubiquitinated TDP-43, are associated with the loss of nuclear function, which, together with gain of toxicity, may contribute to pathological mechanisms. TDP-43 proteinopathy in brain diseases has been ascribed primarily to neurons, with growing evidence implicating also glial cells, including astrocytes, oligodendrocytes (OLs) and microglia. However, the specific role of TDP-43 and the consequences of its loss of function in microglia have been scarcely explored. TDP-43 regulates RNA splicing and suppresses cryptic exons (CEs) inclusion. When TDP-43 is depleted, CEs are spliced into mRNAs, often introducing premature STOP codons and leading to nonsense-mediated decay. The specific exons affected by TDP-43 splicing largely depend on the cellular identity, impacting different molecular pathways based on the cell type in which TDP-43 is dysregulated. While TDP-43-dependent targets have been reported in diverse cell types, the TDP-43-mediated regulation of CE in microglia remains unexplored. Microglia, the innate immune cells of the central nervous system, have important functions in both physiological and pathological contexts. Genome-wide association studies support their implication as risk factors in neurodegeneration, suggesting that microglia may have critical roles in modifying disease onset and severity. Despite increasing evidence, their role in brain diseases remains underexplored. It is unclear whether dysfunctional microglial profiles associated with neurodegeneration could begin affecting the brain during early developmental stages. Given that microglia are essential for proper brain maturation and their impairment during critical developmental windows can have lasting effects on brain function, investigating the role of microglial TDP-43 in brain development is crucial to understanding its potential early contribution to neurodegenerative processes.