Biology subjects

Ganssauge, J.

Publications and source records attributed to Ganssauge, J..

3 recordsLinked to original sources

bioRxiv2026

SNRNP70 interacts with TDP-43 to promote RNP granule localisation and regulate motor neuron development

SNRNP70 is a core spliceosomal protein that localises to both the nucleus and cytoplasm. Previous studies have implicated SNRNP70 in regulating axonal stability and the transport of specific mRNAs during motor neuron development in zebrafish. Although the molecular functions and protein interactions of SNRNP70 in pre-mRNA splicing are well established, the mechanisms underlying its cytoplasmic functions remain poorly understood. Here, we show that SNRNP70 and TDP-43 exhibit similar localisation patterns in developing and mature neurons and co-associate in both nuclear and non-nuclear compartments, including axonal projections. We identify a functional interaction between SNRNP70 and TDP-43 that is essential for motor neuron development and demonstrate that the recruitment of SNRNP70 to cytoplasmic ribonucleoprotein (RNP) granules depends on TDP-43. These findings identify a previously unrecognised cytoplasmic function of TDP-43 in directing SNRNP70-containing RNP granule assembly, thereby linking TDP-43 to the splicing-independent functions of SNRNP70 during motor neuron development.

neuroscience↗

bioRxiv2026

Single-cell transcriptomics uncovers chromatin dysfunction in a human TDP-43 proteinopathy model of Amyotrophic Lateral Sclerosis.

TDP-43 proteinopathy, characterised by nuclear depletion and cytoplasmic aggregation of TDP-43, is the defining pathological hallmark of amyotrophic lateral sclerosis (ALS) and a shared pathology across frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), limbic-predominant age-related TDP-43 encephalopathy (LATE), and a substantial subset of Alzheimers disease. We recently developed a human model of TDP-43 proteinopathy that enables inducible mislocalisation of endogenous TDP-43 in iPSC-derived neurons without chemical stress or mutant protein overexpression. Using single-cell RNA sequencing of this model, we dissected the transcriptomic consequences of TDP-43 nuclear depletion across motor neurons as well as V1 and V2 interneurons at single-cell resolution. This approach uncovered disruption of ATP-dependent chromatin remodelling as a convergent downstream pathway across all three spinal neuron subtypes. Master regulator analysis identified ACTL6B, the neuron-specific subunit of the nBAF (neuronal BRG1/BRM-associated factor) chromatin remodelling complex, as the most consistently inhibited transcription factor following TDP-43 mislocalisation. ACTL6B downregulation emerges early in the mislocalisation cascade and is confirmed in post-mortem ALS spinal cord. ACTL6B knockdown in post-mitotic motor neurons phenocopies both the morphological and transcriptional consequences of TDP-43 pathology. Together, these findings establish nBAF complex dysfunction as a principal, spinal cord-enriched driver of TDP-43-associated neurodegeneration and reveal chromatin remodelling defects as a key mechanism in ALS.

neuroscience↗

bioRxiv2023

Rapid and Inducible Mislocalization of Endogenous TDP43 in a Novel Human Model of Amyotrophic Lateral Sclerosis

Transactive response DNA binding protein 43 kDa (TDP43) proteinopathy, characterized by the mislocalization and aggregation of TDP43, is a hallmark of several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). In this study, we describe the development of a new model of TDP43 proteinopathy using human induced pluripotent stem cell (iPSC)-derived neurons. Utilizing a genome engineering approach, we induced the mislocalization of endogenous TDP43 from the nucleus to the cytoplasm without mutating the TDP43 gene or using chemical stressors. Our model successfully recapitulates key early and late pathological features of TDP43 proteinopathy, including neuronal loss, reduced neurite complexity, and cytoplasmic accumulation and aggregation of TDP43. Concurrently, the loss of nuclear TDP43 leads to splicing defects, while its cytoplasmic gain adversely affects microRNA expression. Strikingly, our observations suggest that TDP43 is capable of sustaining its own mislocalization, thereby perpetuating and further aggravating the proteinopathy. This innovative model provides a valuable tool for the in-depth investigation of the consequences of TDP43 proteinopathy. It offers a clinically relevant platform that will accelerate identification of potential therapeutic targets for the treatment of TDP43-associated neurodegenerative diseases including sporadic ALS.

neuroscience↗