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Gnal or Tor1a mutation leads to shared transcriptional alterations in striatal cellular subtypes in mouse models of dystonia

ABSTRACT: Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent muscle contraction and abnormal postures. Several dystonia-associated mutations have been identified. The common theme across the majority of studies utilizing animal models that recapitulate these mutations have indicated mechanisms of sustained, imperturbable long-term potentiation of corticostriatal synapses in medium spiny neurons (MSNs) and reduced ability to induce long-term depression. This suggests a striato-centric neuronal adaptive response to mutation that may drive disease pathology. However, the cell type-specificity and molecular programs driving these changes are unknown. To address this, we utilized single-nucleus RNA-sequencing on striatal cells extracted from two dystonia mouse models that recapitulate genetic mutations linked to dystonia: DYT1 (Tor1awt/ E) and DYT25 (Gnal+/-). Upon analysis, MSNs exhibited the majority of transcriptional changes: Gnal deficiency was associated with downregulation of genes involved in the maintenance of membrane potential and increased expression of those encoding for neuron development-related molecules. Mice with Tor1awt/ E mutation had enhanced expression of specific immediate early genes (Arc and Npas4) in MSNs. These alterations may drive and/or reflect the altered plasticity mechanisms observed in dystonia. Changes in transcription of several genes in MSNs were shared across both mouse models, including Lrrk2, Reln, and Pkrcb. Further exploration of these and other shared pathways may open new avenues for future investigation of strategies to treat dystonia and other conditions related to GNAL or TOR1A dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE345347 | GEO | 2026/08/31

REPOSITORIES: GEO

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Project description:The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate. The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate.

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Gnal or Tor1a mutation leads to shared transcriptional alterations in striatal cellular subtypes in mouse models of dystonia

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