Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Background:

• Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare neurological disorder.
• Mutations in the colony-stimulating factor-1 receptor (CSF-1R) gene are implicated in HDLS pathogenesis.

Purpose of the Study:

• To investigate the histopathological changes in microglia within the brains of HDLS patients with CSF-1R mutations.
• To clarify the role of microglial alterations in the development of HDLS.

Main Methods:

• Examination of 6 HDLS patient specimens (5 autopsies, 1 biopsy).
• Detailed immunohistochemical, biochemical, and ultrastructural analyses of microglia.
• Quantitative analysis of microglial morphology and protein expression.

Main Results:

• HDLS microglia exhibited altered morphology, with reduced Iba1 immunoreactivity in superficial cortical layers.
• Microglia distribution was uneven in deeper layers and white matter.
• Reduced levels of microglial proteins (CD11b, DAP12) and signs of depressed protein synthesis were observed.
• Macrophages were identified as bone marrow-derived.

Conclusions:

• Microglial vulnerability and morphological changes are associated with HDLS pathogenesis.
• CSF-1R mutations impact microglial function and structure, contributing to the disease.