Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington's Disease and Possible Therapeutic Avenues
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE232649 | GEO | 2025/07/22
REPOSITORIES: GEO
Similar Datasets
Project description:Huntington's Disease (HD) is a neurodegenerative disorder caused by an expansion of CAG repeats in exon 1 of the HTT gene, ultimately resulting in the generation of a mutant HTT (mHTT) protein. Although mHTT is expressed in various tissues, it significantly affects medium spiny neurons (MSNs) in the striatum, resulting in their loss and the subsequent motor function impairment found in HD. While HD symptoms typically emerge in midlife, disrupted MSN neurodevelopment plays an important role. To explore the effects of HD on MSN development, we differentiated induced HD pluripotent stem cells (iPSC) and isogenic control into neuronal stem cells, and then generated a developing MSN population encompassing early, intermediate progenitors, and mature MSNs. Single cell RNA sequencing (scRNAseq) revealed that the developmental trajectory of MSNs in our model closely emulated the trajectory of fetal striatal neurons. However, in the HD MSN cultures, this process was by downregulating several crucial genes for required for proper MSN maturation, including ASCL1 and members of the DLX family of transcription factors. Our analysis also uncovered a progressive dysregulation of multiple HD-related pathways as MSNs matured, including the NRF2-mediated oxidative stress response and ERK/MAPK signaling. Using the transcriptional profile of developing HD MSNs, we searched the L1000 dataset for small molecules that induce an opposite gene expression pattern. Our analysis pinpointed numerous small molecules with known benefits in HD models, as well as previously untested novel molecules. A top novel candidate, Cerulenin, demonstrated a partial restoration of DARPP-32 levels and electrical activity in HD MSNs, while also modulating genes involved in in multiple HD related pathways.
2025-07-22 | GSE232648 | GEO
Project description:Huntington's Disease (HD) is a neurodegenerative disorder caused by an expansion of CAG repeats in exon 1 of the HTT gene, ultimately resulting in the generation of a mutant HTT (mHTT) protein. Although mHTT is expressed in various tissues, it significantly affects medium spiny neurons (MSNs) in the striatum, resulting in their loss and the subsequent motor function impairment found in HD. While HD symptoms typically emerge in midlife, disrupted MSN neurodevelopment plays an important role. To explore the effects of HD on MSN development, we differentiated induced HD pluripotent stem cells (iPSC) and isogenic control into neuronal stem cells, and then generated a developing MSN population encompassing early, intermediate progenitors, and mature MSNs. Single cell RNA sequencing (scRNAseq) revealed that the developmental trajectory of MSNs in our model closely emulated the trajectory of fetal striatal neurons. However, in the HD MSN cultures, this process was by downregulating several crucial genes for required for proper MSN maturation, including ASCL1 and members of the DLX family of transcription factors. Our analysis also uncovered a progressive dysregulation of multiple HD-related pathways as MSNs matured, including the NRF2-mediated oxidative stress response and ERK/MAPK signaling. Using the transcriptional profile of developing HD MSNs, we searched the L1000 dataset for small molecules that induce an opposite gene expression pattern. Our analysis pinpointed numerous small molecules with known benefits in HD models, as well as previously untested novel molecules. A top novel candidate, Cerulenin, demonstrated a partial restoration of DARPP-32 levels and electrical activity in HD MSNs, while also modulating genes involved in in multiple HD related pathways.
2025-07-22 | GSE232646 | GEO
Project description:Huntington's Disease (HD) is a neurodegenerative disorder caused by an expansion of CAG repeats in exon 1 of the HTT gene, ultimately resulting in the generation of a mutant HTT (mHTT) protein. Although mHTT is expressed in various tissues, it significantly affects medium spiny neurons (MSNs) in the striatum, resulting in their loss and the subsequent motor function impairment found in HD. While HD symptoms typically emerge in midlife, disrupted MSN neurodevelopment plays an important role. To explore the effects of HD on MSN development, we differentiated induced HD pluripotent stem cells (iPSC) and isogenic control into neuronal stem cells, and then generated a developing MSN population encompassing early, intermediate progenitors, and mature MSNs. Single cell RNA sequencing (scRNAseq) revealed that the developmental trajectory of MSNs in our model closely emulated the trajectory of fetal striatal neurons. However, in the HD MSN cultures, this process was by downregulating several crucial genes for required for proper MSN maturation, including ASCL1 and members of the DLX family of transcription factors. Our analysis also uncovered a progressive dysregulation of multiple HD-related pathways as MSNs matured, including the NRF2-mediated oxidative stress response and ERK/MAPK signaling. Using the transcriptional profile of developing HD MSNs, we searched the L1000 dataset for small molecules that induce an opposite gene expression pattern. Our analysis pinpointed numerous small molecules with known benefits in HD models, as well as previously untested novel molecules. A top novel candidate, Cerulenin, demonstrated a partial restoration of DARPP-32 levels and electrical activity in HD MSNs, while also modulating genes involved in in multiple HD related pathways.
2025-07-22 | GSE232647 | GEO
Project description:Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington's Disease and Possible Therapeutic Avenues
| PRJNA973090 | ENA
Project description:Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington's Disease and Possible Therapeutic Avenues [scRNA-seq]
| PRJNA973091 | ENA
Project description:Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington's Disease and Possible Therapeutic Avenues [bulk RNA-seq]
| PRJNA973093 | ENA
Project description:Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington's Disease and Possible Therapeutic Avenues [Bulk RNA-seq treated with Cerulenin]
| PRJNA973092 | ENA
Project description:Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is > 40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum.
| S-EPMC3337013 | biostudies-literature
Project description:Dopamine system disorders ranging from movement disorders to addiction and schizophrenia involve striatal medium spiny neurons (MSNs), yet their functional connectivity has been difficult to determine comprehensively. We generated a mouse with conditional channelrhodopsin-2 expression restricted to medium spiny neurons and assessed the specificity and strength of their intrinsic connections in the striatum and their projections to the globus pallidus and the substantia nigra. In the striatum, medium spiny neurons connected with other MSNs and tonically active cholinergic interneurons, but not with fast-spiking GABA interneurons. In the globus pallidus, medium spiny neurons connected strongly with one class of electrophysiologically identified neurons, but weakly with the other. In the substantia nigra, medium spiny neurons connected strongly with GABA, but not with dopamine neurons. Projections to the globus pallidus showed solely D2-mediated presynaptic inhibition, whereas projections to the substantia nigra showed solely D1-mediated presynaptic facilitation. This optogenetic approach defines the functional connectome of the striatal medium spiny neuron.
| S-EPMC3074638 | biostudies-literature
Project description:Slowly varying activity in the striatum, the main Basal Ganglia input structure, is important for the learning and execution of movement sequences. Striatal medium spiny neurons (MSNs) form cell assemblies whose population firing rates vary coherently on slow behaviourally relevant timescales. It has been shown that such activity emerges in a model of a local MSN network but only at realistic connectivities of 10 ~ 20% and only when MSN generated inhibitory post-synaptic potentials (IPSPs) are realistically sized. Here we suggest a reason for this. We investigate how MSN network generated population activity interacts with temporally varying cortical driving activity, as would occur in a behavioural task. We find that at unrealistically high connectivity a stable winners-take-all type regime is found where network activity separates into fixed stimulus dependent regularly firing and quiescent components. In this regime only a small number of population firing rate components interact with cortical stimulus variations. Around 15% connectivity a transition to a more dynamically active regime occurs where all cells constantly switch between activity and quiescence. In this low connectivity regime, MSN population components wander randomly and here too are independent of variations in cortical driving. Only in the transition regime do weak changes in cortical driving interact with many population components so that sequential cell assemblies are reproducibly activated for many hundreds of milliseconds after stimulus onset and peri-stimulus time histograms display strong stimulus and temporal specificity. We show that, remarkably, this activity is maximized at striatally realistic connectivities and IPSP sizes. Thus, we suggest the local MSN network has optimal characteristics - it is neither too stable to respond in a dynamically complex temporally extended way to cortical variations, nor is it too unstable to respond in a consistent repeatable way. Rather, it is optimized to generate stimulus dependent activity patterns for long periods after variations in cortical excitation.
| S-EPMC3623749 | biostudies-literature