Biology subjects

Utami, K. H.

Publications and source records attributed to Utami, K. H..

4 recordsLinked to original sources

bioRxiv2026

Ropinirole hydrochloride mitigates oxidative stress and neuroinflammation via the PI3K-mTOR pathway in TDP-43 hiPSC-derived microglial-like cells

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss accompanied by neuroinflammation, oxidative stress, and impaired proteostasis, with pathological aggregation of TDP-43 as its defining hallmark. Microglia are recognized as central contributors to ALS pathogenesis, yet the mechanisms underlying their intrinsic dysfunction in the context of TDP-43 remain insufficiently characterized. MethodsWe characterized microglia-like cells (iMGLs) differentiated from isogenic TDP-43 M337V human induced pluripotent stem cell lines. We performed integrated functional assays, transcriptomic profiling and drug repurposing analysis to systematically compare mutant and control iMGLs. To assess therapeutic potential, we evaluated the effects of ROPI, a dopamine D2 receptor agonist previously advanced to clinical trials for ALS, on disease-relevant phenotypes in TDP-43 iMGLs. ResultsTDP-43M337V/M337V iMGLs presented ALS-associated abnormalities, including cytoplasmic TDP-43 accumulation with impaired phagocytosis and elevated oxidative stress, impaired autophagy and mitophagy, altered cytokine profiles, and reduced ferritin levels. Building on our previous identification of ropinirole hydrochloride as neuroprotective for ALS motor neurons, we now show that it confers therapeutic benefits in mitigating microglial pathology. ROPI treatment significantly reduced oxidative stress and caspase-3/7 activity and partially restored cytokine homeostasis in TDP-43M337V/M337V iMGLs, independent of autophagy/mitophagy modulation. Transcriptomic profiling revealed that ropinirole modulated disease-associated gene expression signatures involving protein folding, extracellular matrix organization, and oxidative stress responses. Furthermore, connectivity map-based analysis prioritized PI3K-Akt-mTOR inhibitors as candidates for reversing TDP-43 iMGL signatures, and ropinirole was found to modulate mTOR signaling. These converging lines of evidence support a mechanistic role for ropinirole in restoring microglial homeostasis via PI3K-mTOR pathway regulation. Taken together, our findings position ropinirole as a promising candidate dual action therapeutic candidate capable of targeting both neuronal and microglial dysfunction in ALS, suggesting broader applicability of ropinirole in modulating neuroinflammatory cascades across other neurodegenerative conditions. ConclusionRopinirole broadens ALS therapy from motor neurons to microglia, underscoring its promise for integrated and clinically meaningful treatment strategies.

neuroscience↗

bioRxiv2022

Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington's disease

In Huntingtons disease (HD), a CAG repeat expansion mutation in the HTT gene drives a gain-of-function toxicity that disrupts mRNA processing. Although widespread dysregulation of gene splicing in the striatum has been shown in human HD post-mortem brain tissue, post-mortem analyses are likely confounded by cell type composition changes due to neuronal loss and astrogliosis in late stage HD. This limits the ability to identify dysregulation related to early pathogenesis. To study alternative splicing changes in early HD, we performed RNA-sequencing analysis in an established isogenic HD neuronal cell model. We report cell type-associated and CAG length-dependent splicing changes, and find an enrichment of RNA processing genes coupled with neuronal function-related genes showing mutant HTT-associated splicing changes. Comparison with post-mortem data also identified splicing events associated with early pathogenesis that persist to later stages of disease. In summary, our results highlight splicing dysregulation in RNA processing genes in early and late-stage HD, which may lead to disrupted neuronal function and neuropathology.

neuroscience↗

bioRxiv2019

Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

Huntington disease (HD) manifests in both adult and juvenile forms. Mutant HTT gene carriers are thought to undergo normal brain development followed by a degenerative phase, resulting in progressive clinical manifestations. However, recent studies in children and prodromal individuals at risk for HD have raised the possibility of abnormal neurodevelopment. Although key findings in rodent models support this notion, direct evidence in the context of human physiology remains lacking. Using a panel of isogenic HD human embryonic pluripotent stem cells and cerebral organoids, we investigated the impact of mutant HTT on early neurodevelopment. We find that ventricular zone-like neuroepithelial progenitor layer expansion is blunted in an HTT CAG repeat length-dependent manner due to premature neurogenesis in HD cerebral organoids, driven by cell intrinsic processes. Transcriptional profiling and imaging analysis revealed impaired cell cycle regulatory processes, increased G1 length, and increased asymmetric division of apical progenitors, collectively contributing to premature neuronal differentiation. We demonstrate increased activity of the ATM-p53 pathway, an up-stream regulator of cell cycle processes, and show that treatment with ATM antagonists partially rescues the blunted neuroepithelial progenitor expansion in HD organoids. Our findings suggest that CAG repeat length regulates the balance between neural progenitor expansion and differentiation during early neurodevelopment. Our results further support the view that HD, at least in its early-onset forms, may not be a purely neurodegenerative disorder, and that abnormal neurodevelopment may be a component of HD pathophysiology.

developmental biology↗

bioRxiv2019

Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in Fragile X Syndrome

Fragile X syndrome (FXS) is an incurable neurodevelopmental disorder with no effective treatment. FXS is caused by epigenetic silencing of FMR1 and loss of FMRP expression. To investigate the consequences of FMRP deficiency in the context of human physiology, we established isogenic FMR1 knockout (FMR1KO) human embryonic stem cells (hESCs). Integrative analysis of the transcriptomic and proteomic profiles of hESC-derived FMRP-deficient neurons revealed several dysregulated pathways important for brain development including processes related to axon development, neurotransmission, and the cell cycle. We functionally validated alterations in a number of these pathways, showing abnormal neural rosette formation and increased neural progenitor cell proliferation in FMR1KO cells. We further demonstrated neurite outgrowth and branching deficits along with impaired electrophysiological network activity in FMRP-deficient neurons. Using isogenic FMR1KO hESC-derived neurons, we reveal key molecular signatures and neurodevelopmental abnormalities arising from loss of FMRP. We anticipate that the FMR1KO hESCs and the neuronal transcriptome and proteome datasets will provide a platform to delineate the pathophysiology of FXS in human neural cells.

neuroscience↗