Biology subjects

Yoo, A. S.

Publications and source records attributed to Yoo, A. S..

5 recordsLinked to original sources

bioRxiv2026

The human-specific lncRNA HD-LINC drives lipid droplet-associated neurodegeneration in Huntington's disease

Huntington's disease (HD) is characterized by degeneration of striatal medium spiny neurons (MSNs), yet the human-specific regulatory mechanisms that contribute to neuronal vulnerability remain poorly understood. Here, we identify HD-LINC (LINC01139), a human-specific long intergenic noncoding RNA selectively induced in symptomatic HD patient-derived MSNs (HD-MSNs) and human HD caudate. Single-cell transcriptomic analysis in HD-MSNs revealed that HD-LINC was enriched in a symptomatic HD neuronal state associated with lipid metabolic and protein clearance regulation, while not observed in non-degenerative reprogrammed MSNs derived from pre-manifest HD individuals. Reducing HD-LINC attenuated mutant HTT aggregation, dystrophic neurites, DNA damage, and neuronal death, whereas HD-LINC overexpression exacerbated these phenotypes. Transcriptomic and lipidomic analyses further implicated HD-LINC in neuronal lipid regulation. We found that HD-MSNs exhibited aberrant accumulation of enlarged, low-mobility lipid droplets (LDs) within neurites, a previously unrecognized phenotype in patient-derived neurons. Critically, increased lipid peroxidation was observed within LD-enriched dystrophic neurites in HD-MSNs. HD-LINC knockdown cleared neuritic LD accumulation, restored soma-enriched LD distribution, and reduced lipid peroxidation. Finally, we developed antisense oligonucleotides that effectively reduced HD-LINC and reversed HD-LINC-associated phenotypes, nominating HD-LINC lowering as a potential therapeutic strategy in HD. These results identify HD-LINC as a human-specific regulator of neuronal LD spatial organization, lipid peroxidation, and neuronal degeneration in HD. They further reveal dysregulated neuritic LD accumulation driven by HD-LINC, and highlight lincRNA-mediated lipid dysregulation as a significant contributor to neuronal vulnerability to degeneration.

neuroscience↗

bioRxiv2026

Large-scale Perturbation of Systems Biology-Derived Genes Reveals Modifiers of HD-associated Transcriptomic Networks and Pathology

In Huntingtons disease (HD), disease-driver genes are broadly expressed, but pathogenic players specific to vulnerable neurons remain poorly defined. Leveraging a previously defined mutant huntingtin (mHtt) CAG-length-associated gene network, we perturbed 115 module hub genes with heterozygous knockout (KO-het) to assess their striatal transcriptomic modifier effects in wildtype and Q140 HD mice. We generated 3,592 striatal RNA-seq datasets, mapped 6,517 perturbagen-responder gene pairs, and uncovered regulators of medium spiny neuron (MSN) identity gene expression and DNA- methylase/demethylase-sensitive genes. We developed a bioinformatic pipeline to rank the perturbations with significant impacts on striatal transcriptome and HD-associated gene networks in wildtype or Q140 mice. KO-het for FoxP1 and Scn4b (two MSN-selective genes) exacerbated, whereas Pdp1 KO-het ameliorated, Q140 striatal pathology. Importantly, knockdown of functionally opposing ion channels, SCN4B and KCNH4, dichotomously affected aggregation and neurodegeneration in reprogrammed HD patient MSNs. Together, our study rigorously evaluated systems biology-derived candidates to identify modifiers of HD-associated molecular networks and pathology, providing an in vivo perturbation- transcriptome resource and highlighting genes involved in MSN excitability, transcription, calcium signaling, and mitochondrial metabolism in HD pathogenesis.

genetics↗

bioRxiv2025

Sequelae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons

How aging of human neurons affects dynamics of essential organelle such as mitochondria and autophagosomes remains largely unknown. MicroRNA-induced directly reprogrammed neurons (miNs) derived from adult fibroblasts retain age-associated signatures of the donor, enabling the study of age-dependent features in human neurons, including longitudinal isogenic samples. Transcriptomic analysis revealed that neurons derived from elderly individuals are characterized by gene expression changes associated with the regulation of autophagosomes, lysosomes, and mitochondria, compared to young counterparts. To clarify these changes at the cellular level, we performed live-cell imaging of cellular organelles in miNs from donors of different ages. Older donor miNs exhibit decreased mitochondrial membrane potential, which surprisingly co-occurs with a significant increase in mitochondrial fission and fusion events. We posit that the increased fission and fusion of mitochondria may reflect age-dependent compensation for impaired mitochondrial turnover, perhaps due to changes in autophagy. We subsequently identified a significant decrease in autophagosome acidification in neurons derived from individuals >65 years compared to younger donors, and a corresponding age-dependent reduction in neuritic lysosomes resulting in fewer lysosomes available to acidify autophagosomes. This age-dependent deficit in autolysosome flux was rescued by promoting autophagosome generation through TFEB, which also reversed the age-dependent increase in mitochondrial fission and fusion and improved mitochondrial health. Partial organelle recovery occurred after inducing mitophagy or inhibiting mitochondrial fission. Together, this work reveals a mechanism by which aging reduces autophagic flux secondary to a loss of neuritic lysosomes, resulting in in mitochondria-intrinsic mechanisms to avoid loss of energy production.

neuroscience↗

bioRxiv2023

Endogenous recapitulation of Alzheimers disease neuropathology through human 3D direct neuronal reprogramming

Alzheimers disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-{beta} (A{beta}) plaque deposition, intracellular tau tangles, and neuronal death. However, recapitulating these age-associated neuronal pathologies in patient-derived neurons has remained a significant challenge, especially for late-onset AD (LOAD), the most common form of the disorder. Here, we applied the high efficiency microRNA-mediated direct neuronal reprogramming of fibroblasts from AD patients to generate cortical neurons in three-dimensional (3D) Matrigel and self-assembled neuronal spheroids. Our findings indicate that neurons and spheroids reprogrammed from both autosomal dominant AD (ADAD) and LOAD patients exhibited AD-like phenotypes linked to neurons, including extracellular A{beta} deposition, dystrophic neurites with hyperphosphorylated, K63-ubiquitin-positive, seed-competent tau, and spontaneous neuronal death in culture. Moreover, treatment with {beta}- or {gamma}-secretase inhibitors in LOAD patient-derived neurons and spheroids before A{beta} deposit formation significantly lowered A{beta} deposition, as well as tauopathy and neurodegeneration. However, the same treatment after the cells already formed A{beta} deposits only had a mild effect. Additionally, inhibiting the synthesis of age-associated retrotransposable elements (RTEs) by treating LOAD neurons and spheroids with the reverse transcriptase inhibitor, lamivudine, alleviated AD neuropathology. Overall, our results demonstrate that direct neuronal reprogramming of AD patient fibroblasts in a 3D environment can capture age-related neuropathology and reflect the interplay between A{beta} accumulation, tau dysregulation, and neuronal death. Moreover, miRNA-based 3D neuronal conversion provides a human-relevant AD model that can be used to identify compounds that can potentially ameliorate AD-associated pathologies and neurodegeneration.

neuroscience↗

bioRxiv2020

Synergism between microRNA-124 and ELAVL3 drives neuronal gene upregulation during direct neuronal reprogramming of human fibroblasts

Neuron-enriched microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124), direct cell fate switching of human fibroblasts to neurons when ectopically expressed by repressing anti-neurogenic genes. How these miRNAs function after the onset of the transcriptome switch to a neuronal fate remains unclear. Here, we identified direct targets of miRNAs by Argonaute (AGO) HITS-CLIP as reprogramming cells activate the neuronal program and reveal the role of miR-124 that directly promotes the expression of its target genes associated with neuronal development and function. The mode of miR-124 as a positive regulator is determined by a neuron-enriched RNA-binding protein, ELAVL3, that interacts with AGO and binds target transcripts, whereas the non-neuronal ELAVL1 counterpart fails to elevate the miRNA-target gene expression. Although existing literature indicate that miRNA-ELAVL1 interaction can result in either target gene upregulation or downregulation in a context-dependent manner, we specifically identified neuronal ELAVL3 as the driver for miRNA target gene upregulation in neurons. In primary human neurons, repressing miR-124 and ELAVL3 led to the downregulation of genes involved in neuronal function and process outgrowth, and cellular phenotypes of reduced inward currents and neurite outgrowth. Results from our study support the role of miR-124 promoting neuronal function through positive regulation of its target genes.

neuroscience↗