Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Neurodegeneration involves progressive neuronal death.
• Understanding cell-type specific contributions is crucial for disease mechanisms.

Purpose of the Study:

• To dissect cell-type specific roles in spinocerebellar ataxia type 1 (SCA1) pathogenesis.
• To identify early transcriptional changes preceding neuronal loss in SCA1.

Main Methods:

• Longitudinal single-nucleus RNA sequencing of mouse and human SCA1 cerebellar tissue.
• Deep learning for disease state prediction and feature identification.

Main Results:

• Established dynamic transcriptional trajectories for individual cell populations.
• Identified early transcriptional dysregulation in unipolar brush cells and oligodendroglia preceding Purkinje cell loss.
• Developed a deep learning model to accurately distinguish wild-type and SCA1 cells.

Conclusions:

• Reveals novel roles for diverse cerebellar cell types in SCA1.
• Provides a generalizable computational framework for neurodegeneration research.