Ropinirole improves the amyotrophic lateral sclerosis phenotype of TDP43-mutant iPSC-derived motor neurons via a D2R-independent mechanism
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ABSTRACT:
PROVIDER: PRJNA1194128 | ENA |
REPOSITORIES: ENA
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Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron (MN) degeneration. The dopamine D2 receptor (D2R, DRD2) agonist ropinirole hydrochloride (ROPI) constitutes a potential therapeutic candidate for ALS through phenotypic screening of disease models of MNs that use patient-derived induced pluripotent stem cells (iPSCs). The ROPALS trial, a phase I/II trial in patients with ALS, demonstrated the safety and efficacy of ROPI. However, the D2R antagonist and modulator only partially mitigated the suppressive effect of ROPI on the ALS phenotype, and the detailed mechanism of action of ROPI has not been fully elucidated. In this study, we investigated whether the therapeutic effects of ROPI in ALS depend on D2R. Using D2R-deficient iPSCs, we demonstrated that ROPI effectively mitigated neuronal cell death, reactive oxygen species (ROS) production, and neuronal hyperexcitation in a D2R-independent manner. Further analyses revealed that ROPI rescued aberrant RNA splicing and restored mRNA expression of mitochondrial proteins in a D2R-independent manner. Our data suggest that ROPI has not only a canonical D2R agonist effect, but also multifunctional effects that are mediated in a D2R-independent manner. Therefore, our findings may open new avenues for the development of more effective therapeutic approaches for ALS.
2025-08-27 | GSE283507 | GEO
Project description:A consistent clinical feature of amyotrophic lateral sclerosis (ALS) is the sparing of eye movements. Pathological studies have confirmed that there is relative sparing of the cranial motor nuclei of the oculomotor, trochlear and abducens nerves, although pathological changes resembling those seen in anterior horn cells are present to a lesser degree. The aim of the present study is to combine LCM and microarray analysis to study the differences between motor neurons that are selectively resistant (oculomotor neurons) and those that are vulnerable (lumbar spinal motor neurons) to the disease process in amyotrophic lateral sclerosis. We used microarray analysis to determine the differences in gene expression between oculomotor and lumbar spinal motor neurons, isolated by laser capture microdissection from the midbrain and spinal cord of neurologically normal human controls.
2013-03-01 | E-GEOD-40438 | biostudies-arrayexpress
Project description:A consistent clinical feature of amyotrophic lateral sclerosis (ALS) is the sparing of eye movements. Pathological studies have confirmed that there is relative sparing of the cranial motor nuclei of the oculomotor, trochlear and abducens nerves, although pathological changes resembling those seen in anterior horn cells are present to a lesser degree. The aim of the present study is to combine LCM and microarray analysis to study the differences between motor neurons that are selectively resistant (oculomotor neurons) and those that are vulnerable (lumbar spinal motor neurons) to the disease process in amyotrophic lateral sclerosis.
2013-03-01 | GSE40438 | GEO
Project description:Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder primarily characterized by motor neuron degeneration with additional involvement of non-neuronal cells, in particular, microglia. In our previous work, we have established protocols for the differentiation of iPSC-derived spinal motor neurons and microglia. Here, we combine both cell lineages and establish a novel co-culture of iPSC-derived motor neurons and microglia, which is compatible with motor neuron identity and function. Co-cultured microglia express key microglial markers and transcriptomically resemble primary human microglia, have highly dynamic ramifications, are phagocytic, release various cytokines and respond to stimulation. Further, they express key amyotrophic lateral sclerosis-associated genes and release disease-relevant biomarkers. This novel and authentic human model system facilitates the study of physiological motor neuron-microglia crosstalk and permits the investigation of non-cell-autonomous phenotypes in amyotrophic lateral sclerosis.
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Project description:Identification of familial amyotrophic lateral sclerosis (fALS) related genes. Material from three hSOD1(G93A) transgenic mice was compared to material from three non-transgenic control mice using an alternating loop design on two-colour cDNA microarrays. Statistical data management and analysis: postgreSQL relational database (www.postgresql.org), Perl, and R (www.r-project.org); pin-wise lowess-regression based normalisation (Yang et al., 2002 [PMID: 11842121]); mixed ANOVA-model. Keywords = amyotrophic lateral sclerosis, ALS, SOD1 mouse model
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