Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U

Area of Science:

• Neuroscience
• Genomics
• Pathology

Background:

• Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare FTLD subtype characterized by FTLD-FET protein inclusions.
• Understanding the etiology of aFTLD-U is limited, hindering diagnostic and therapeutic advancements.

Purpose of the Study:

• To investigate the transcriptomic changes in the frontal cortex of aFTLD-U patients.
• To identify molecular pathways and cell types involved in aFTLD-U pathogenesis.

Main Methods:

• Bulk RNA sequencing was performed on frontal cortex tissue from 21 aFTLD-U patients and 20 controls.
• Cell-type deconvolution, differential gene expression, co-expression network analysis, and differential splicing analysis were employed.
• Immunohistochemistry was used to assess myelin levels.

Main Results:

• aFTLD-U brains showed a loss of excitatory neurons and an increased proportion of astrocytes.
• Dysregulated mitochondrial pathways, transcriptional regulators, and the Sonic hedgehog (Shh) pathway (including GLI1) were identified.
• Genes enriched in oligodendrocytes and astrocytes were over-represented among differentially expressed genes, with significant splicing alterations in oligodendrocyte genes like myelin basic protein (MBP).
• Reduced myelin levels were observed in aFTLD-U patients.

Conclusions:

• Glial cells, especially astrocytes and oligodendrocytes, play a central role in aFTLD-U pathogenesis.
• Disruptions in mitochondrial activity, RNA metabolism, Shh signaling, and myelination are potential disease mechanisms.
• This study provides the first transcriptomic insights into aFTLD-U, opening new research avenues for FTLD-FET.