Deciphering glial contributions to CSF1R-related disorder via single-nuclear transcriptomic profiling: a case study

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• CSF1R-related disorder (CSF1R-RD) is a neurodegenerative condition affecting white matter, linked to genetic alterations in the CSF1R gene expressed by microglia.
• An elderly patient presented with a progressive dementing disorder, initially negative for common leukodystrophies and neurodegenerative conditions.

Purpose of the Study:

• To investigate the underlying mechanisms of white matter degeneration in a patient with suspected CSF1R-RD.
• To identify the genetic cause and cellular pathology in a case of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

Main Methods:

• Brain autopsy to identify pathological features consistent with ALSP/CSF1R-RD.
• Long-read sequencing to detect genetic alterations in the CSF1R gene.
• Single nuclear RNA sequencing (snRNAseq) to characterize cell states in affected brain regions.

Main Results:

• Autopsy revealed ALSP features, confirming CSF1R-RD. A novel CSF1R deletion, missed by short-read sequencing, was identified.
• Decreased CSF1R transcript and protein levels were observed across brain regions.
• snRNAseq identified distinct disease-associated microglia states (lipid-laden and inflammatory) and impaired oligodendrocyte precursor cell (OPC) differentiation.

Conclusions:

• CSF1R dysfunction drives specific microglial states and hinders OPC differentiation, leading to oligodendrocyte depletion and white matter degeneration.
• Microglia-oligodendroglia crosstalk is a key mechanism in demyelination in CSF1R-RD.
• Long-read sequencing is crucial for detecting complex genetic variants like deletions in CSF1R-RD.