Progranulin Deficiency Induces Mitochondrial Dysfunction in Frontotemporal Lobar Degeneration with TDP-43 Inclusions

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Loss-of-function mutations in the GRN gene, encoding progranulin (PGRN), cause frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), a common early-onset dementia.
• The pathogenesis of FTLD-TDP is not fully understood, though mitochondrial dysfunction is implicated in other neurodegenerative diseases.

Purpose of the Study:

• To investigate the role of mitochondrial alterations in the pathogenesis of PGRN deficiency-associated FTLD-TDP.
• To explore potential therapeutic strategies targeting TDP-43 pathology.

Main Methods:

• Utilized GRN knockdown (KD) SH-SY5Y neuroblastoma cells and lymphoblasts from FTLD-TDP patients with a GRN mutation.
• Assessed mitochondrial function, including depolarization, ROS production, ATP levels, mitochondrial mass, fission, and mitophagy.
• Treated PGRN-deficient cells with brain-penetrant CK-1δ inhibitors.

Main Results:

• PGRN deficiency induced mitochondrial depolarization, increased ROS production, and lowered ATP levels in cells and patient lymphoblasts.
• Mitochondrial damage led to increased mitochondrial fission and mitophagy, alongside elevated mitochondrial mass and autophagy dysfunction.
• CK-1δ inhibitors rescued mitochondrial function in PGRN-deficient cells.

Conclusions:

• Mitochondrial dysfunction is a key feature of FTLD-TDP associated with GRN mutations.
• TDP-43 pathology linked to PGRN deficiency contributes to mitochondrial dysfunction.
• Targeting TDP-43 pathology with CK-1δ inhibitors shows promise for restoring mitochondrial function in FTLD-TDP.