Progranulin deficiency does not exacerbate TDP-43 pathology in TDP-43 transgenic mouse models

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Progranulin (PGRN) is linked to TDP-43 proteinopathy in neurodegenerative diseases.
• The precise regulatory role of PGRN in TDP-43 proteinopathy is not fully understood.

Purpose of the Study:

• To investigate the impact of PGRN deficiency on TDP-43 pathology in mouse models.
• To explore how PGRN loss affects glial activation, behavior, and molecular pathways associated with TDP-43 mutations.

Main Methods:

• Utilized TDP-43^Q331K knock-in mice and human TDP-43 transgenic mice.
• Conducted RNA-sequencing (RNA-seq) to analyze gene expression changes.
• Assessed behavioral deficits, glial activation, and myelination defects.

Main Results:

• PGRN deficiency caused mild glial activation and behavioral deficits in TDP-43^Q331K mice, without typical TDP-43 pathology.
• RNA-seq revealed upregulated immune and downregulated myelination pathways in PGRN-deficient TDP-43^Q331K mice.
• PGRN loss did not worsen TDP-43 pathology, myelination defects, or motor deficits in human TDP-43 transgenic mice.

Conclusions:

• PGRN deficiency exacerbates behavioral deficits and glial pathology in TDP-43^Q331K mice.
• PGRN has a minimal effect on TDP-43 pathology in the studied mouse models.
• Findings highlight a complex interaction between PGRN and TDP-43-related neurodegeneration.