Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics.

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Huntington's disease (HD) is characterized by extensive cellular dysregulation.
• Previous transcriptomic studies offered cell-type insights but lacked spatial resolution.
• Understanding HD's spatial and temporal molecular changes is crucial for mechanism elucidation.

Purpose of the Study:

• To investigate regional, temporal, and cell-type-specific gene expression changes in HD.
• To identify early molecular events and pathways involved in HD pathogenesis.
• To integrate spatial transcriptomics with single-nuclei RNA sequencing for comprehensive analysis.

Main Methods:

• Utilized 10× Genomics Visium spatial transcriptomics on the R6/2 mouse model at P0, 4, and 12 weeks.
• Integrated spatial data with matched single-nuclei RNA sequencing (snRNA-seq) data.
• Analyzed gene expression patterns to identify cell-type-specific and regional alterations.

Main Results:

• Observed broad synaptic dysfunction and early dysregulation of Transcription Factor 4 (Tcf4) in cortical regions.
• Identified mitochondrial deficits as the earliest changes, starting at P0 in the striatum.
• Documented progressive downregulation of striatal identity genes and time-dependent dysregulation of neuropeptide Y signaling.

Conclusions:

• Spatial transcriptomics reveals distinct regional and temporal gene expression patterns in HD.
• Early mitochondrial deficits and synaptic dysfunction are key pathological features.
• Dysregulation of specific pathways, including Tcf4 and neuropeptide Y signaling, contributes to HD progression and neuronal vulnerability.