Modeling hereditary diffuse leukoencephalopathy with axonal spheroids using microglia-sufficient brain organoids

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a fatal adult-onset neurodegenerative disease.
• Mutations in the colony stimulating factor-1 receptor (CSF-1R) gene are the most common cause of HDLS.
• The role of CSF-1R in human microglia and its impact on neuronal health in HDLS remains incompletely understood.

Purpose of the Study:

• To investigate how CSF-1R mutations affect human microglia function.
• To determine the downstream consequences of microglial dysfunction on neuronal cells in HDLS.
• To identify key molecular mechanisms driving neurodegeneration in HDLS.

Main Methods:

• Generation of induced pluripotent stem cells (iPSCs) from HDLS patients and isogenic controls.
• Co-culture system of patient-derived macrophages and forebrain organoids.
• Analysis of macrophage metabolism, inflammatory phenotype, and gene expression (RNA sequencing).

Main Results:

• Patient-derived macrophages (iMacs) exhibited a metabolic shift towards glycolysis and reduced CSF-1 sensitivity.
• iMacs displayed an activated inflammatory phenotype with increased IL-1β production.
• Bulk RNA sequencing revealed a reactive state in iMacs, leading to impaired regulation of neuronal populations in organoid cultures.

Conclusions:

• Microglial dysregulation, particularly elevated IL-1β production, is a key contributor to the neurodegenerative environment in HDLS.
• CSF-1R mutations directly impact microglial function, leading to detrimental effects on neuronal cells.
• This study identifies specific pathways involved in HDLS pathogenesis, offering potential therapeutic targets.