Systemic loss of Rubicon aggravates pathological features in the SOD1G93A mouse model
- 1Center for Integrative Biology, Faculty of Science, Universidad Mayor
- 2Center for Biomedicine (CBM), Facultad de Medicina y Ciencias de la Salud, Universidad Mayor
- 3Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron death. Superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial and sporadic ALS, where either mutant or wild-type SOD1 species abnormally accumulate as observed in postmortem tissue of ALS cases. These SOD1 species are toxic and contribute to motoneuron cell death. A dysregulation of the autophagy pathway has been widely observed in ALS. Previously, we found that Rubicon, a negative regulator of autophagy and endocytosis was upregulated in postmortem spinal cord tissue from sporadic ALS patients and in two ALS mouse models during the symptomatic stage of the disease. Here we found that overexpression of Rubicon in a motoneuron cell line led to marked increase in mutant SOD1 aggregation. Hence, we investigated the effects of Rubicon loss of function in the context of the SOD1G93A ALS mouse model on disease progression and outcome. SOD1G93A/Rub−/− mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1G93A/Rub+/+ mice. Although we observed motor function loss in phenotypic analyses, no changes in microgliosis, astrogliosis, the number of motor neurons or levels of misfolded SOD1 aggregates were detected in vivo. Nevertheless, in vitro experiments showed Rubicon loss-of function in a motor neuron cell line increased mutant SOD1 aggregation, just like its overexpression, however with no adverse effect on motor neuron viability. These results suggest that Rubicon loss-of-function has unforeseen detrimental effects in vivo, highlighting a requirement for a cell-type specific fine-tuned balance of autophagy regulators.
Related
- Primary pulmonary NUT carcinoma: pathological features, clinical diagnosis, treatment, and prognosis — An extended review
- Ultrastructural pathological features and clinical significance of recurrent chordoma
- Inter-organ interaction axes in systemic inflammation: network pathological mechanisms, pharmacological targets, and precision treatment strategies
- Systemic Metastatic Progression of Canine Mammary Comedocarcinoma with Pathological Femoral Fracture: A Case Report.
- Macrophages and immunometabolism in diminished ovarian reserve: pathological features and therapeutic implications.
BibTeX
@article{rodriguez2026systemic,
title = {{Systemic loss of Rubicon aggravates pathological features in the SOD1G93A mouse model}},
author = {Leonardo Rodriguez and Patricia Ojeda and Sebastian Beltran and Ernesto Muñoz-Palma and Diego Rojas-Rivera and Cristian A. Bergmann and Fernanda Hernandez and Danilo B. Medinas and Patricio A. Manque and Ute Woehlbier},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-61046-z},
url = {https://doi.org/10.1038/s41598-026-61046-z},
note = {CC BY},
}
RIS
TY - JOUR
TI - Systemic loss of Rubicon aggravates pathological features in the SOD1G93A mouse model
AU - Leonardo Rodriguez
AU - Patricia Ojeda
AU - Sebastian Beltran
AU - Ernesto Muñoz-Palma
AU - Diego Rojas-Rivera
AU - Cristian A. Bergmann
AU - Fernanda Hernandez
AU - Danilo B. Medinas
AU - Patricio A. Manque
AU - Ute Woehlbier
PY - 2026
DA - 2026/07/01
JO - Scientific Reports
DO - 10.1038/s41598-026-61046-z
UR - https://doi.org/10.1038/s41598-026-61046-z
AB - Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron death. Superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial and sporadic ALS, where either mutant or wild-type SOD1 species abnormally accumulate as observed in postmortem tissue of ALS cases. These SOD1 species are toxic and contribute to motoneuron cell death. A dysregulation of the autophagy pathway has been widely observed in ALS. Previously, we found that Rubicon, a negative regulator of autophagy and endocytosis was upregulated in postmortem spinal cord tissue from sporadic ALS patients and in two ALS mouse models during the symptomatic stage of the disease. Here we found that overexpression of Rubicon in a motoneuron cell line led to marked increase in mutant SOD1 aggregation. Hence, we investigated the effects of Rubicon loss of function in the context of the SOD1G93A ALS mouse model on disease progression and outcome. SOD1G93A/Rub−/− mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1G93A/Rub+/+ mice. Although we observed motor function loss in phenotypic analyses, no changes in microgliosis, astrogliosis, the number of motor neurons or levels of misfolded SOD1 aggregates were detected in vivo. Nevertheless, in vitro experiments showed Rubicon loss-of function in a motor neuron cell line increased mutant SOD1 aggregation, just like its overexpression, however with no adverse effect on motor neuron viability. These results suggest that Rubicon loss-of-function has unforeseen detrimental effects in vivo, highlighting a requirement for a cell-type specific fine-tuned balance of autophagy regulators.
SN - 2045-2322
ER -