C9orf72 is required for proper macrophage and microglial function in mice

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• Hexanucleotide repeat expansions in the C9orf72 gene are the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Reduced C9orf72 expression in carriers suggests a loss-of-function mechanism contributes to disease pathogenesis.

Purpose of the Study:

• To investigate the in vivo function of C9orf72 and its role in neurodegenerative diseases.
• To determine if loss of C9orf72 function leads to motor neuron disease or other pathologies.

Main Methods:

• Generation and analysis of two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik).
• Assessment of normal development, aging, and disease phenotypes in C9orf72 null mice.
• Analysis of C9orf72 expression patterns, particularly in myeloid cells.
• Investigation of lysosomal function and immune responses in macrophages and microglia from C9orf72 null mice.
• Comparison of neuroinflammation in C9orf72 null mice with human ALS patient tissues.

Main Results:

• C9orf72 null mice developed normally and did not exhibit motor neuron disease.
• Progressive splenomegaly and lymphadenopathy were observed, characterized by the accumulation of engorged macrophage-like cells.
• C9orf72 expression was highest in myeloid cells.
• Loss of C9orf72 resulted in lysosomal accumulation and altered immune responses in macrophages and microglia.
• Age-related neuroinflammation was detected in C9orf72 null mice, resembling that seen in C9orf72-linked ALS but not sporadic ALS.

Conclusions:

• C9orf72 is essential for the normal function of myeloid cells.
• Altered microglial function due to C9orf72 deficiency may contribute to neurodegeneration in C9orf72 expansion carriers.
• The study highlights a potential non-neuronal cell-autonomous role for C9orf72 in immune homeostasis relevant to ALS and FTD pathogenesis.