Biology subjects

Campos-Melo, D.

Publications and source records attributed to Campos-Melo, D..

3 recordsLinked to original sources

bioRxiv2026

ARPP21 defines a TDP-43-independent aggregation pathway in amyotrophic lateral sclerosis

Currently, pathological inclusions of ubiquitinated TDP-43 are considered central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, this view has yielded sparse attention to covert alternative pathways of aggregation in the disease. Here, we identified a pathological axis independent of TDP-43 led by ARPP21, a SUZ domain-containing RNA-binding protein encoded by a gene recently described in strong association with ALS. ARPP21 showed large fibrillar non-ubiquitinated aggregates in all the non-SOD1 ALS cases studied, consistently segregating from TDP-43 pathology. Biophysically, ARPP21 undergoes spontaneous phase separation, with a higher propensity for condensate formation than TDP-43 but without co-aggregating with it. ARPP21 also exhibited very slow soluble behavior and lower condensate dynamics compared to TDP-43, an effect that was more pronounced for the ARPP21-P529L disease-related variant. In human iPSC-derived motor neurons, expression of ARPP21 variants was sufficient to drive condensate formation and reduce cell viability. Mechanistically, ARPP21 promoted intercellular propagation by inducing tunnelling nanotube formation, enabling efficient cell-to-cell spreading of aggregates. Genetic analyses further identified multiple ARPP21 variants in ALS, supporting its clinical relevance. Together, our findings uncover ARPP21 as a previously unrecognized TDP-43-independent aggregation pathway in ALS, with implications for disease heterogeneity and therapeutic targeting.

neuroscience↗

bioRxiv2025

3' UTR variants of ALS-linked RNAs modify subcellular and cellular phenotypes

While most human genes express mRNA 3untranslated region (3UTR) variants of different lengths, their impact on cell physiology and disease remains largely unknown. Here, we studied 3UTR length heterogeneity in amyotrophic lateral sclerosis (ALS) and determined that three ALS-linked transcripts exhibit lengthening of their 3UTRs in patient samples. We investigated phenotypical effects in a neuronal cell line expressing these 3UTRs and observed that expression of these unique 3UTRs induces morphological changes at different levels. Among the most expressed 3UTRs variants in ALS, NEFH 3UTR-Long induces the formation of nuclear RNA clusters and SOD1 3UTR-Long diminishes filopodia in the plasma membrane. SQSTM1 3UTR-Long did not show major changes in nuclear RNA clusters or filopodia. This is the first report that suggests that 3UTRs may function independent of the coding region and modify the phenotype of a cell, further expanding the impact of alterations in mRNA biogenesis in ALS.

molecular biology↗

bioRxiv2023

Mitigation of TDP-43-induced toxic phenotype by expression of RGNEF N-terminal fragment in ALS models

Aggregation of the RNA-binding protein (RBP) TDP-43 is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Since TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein (GEF (guanine exchange factor) and RBP) rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that a N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs (RRM) of TDP-43 competing with RNA, and that the IPT/TIG domain of NF242 is essential for this interaction. Genetical expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects, and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with affinity for TDP-43, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.

neuroscience↗