Parkin Levels Decrease in Fibroblasts With Progranulin (PGRN) Pathogenic Variants and in a Cellular Model of PGRN...

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are linked to TDP-43 proteinopathy.
• Progranulin (PGRN) gene variants are a known cause of genetic FTLD and ALS.
• Parkin, a key mitophagy regulator, is depleted in sporadic ALS and TDP-43 models.

Purpose of the Study:

• Investigate parkin levels in FTLD patients with PGRN variants.
• Determine the relationship between PGRN, TDP-43, and parkin in FTLD pathogenesis.
• Explore the role of TDP-43 loss-of-function in parkin downregulation.

Main Methods:

• Analyzed parkin levels in fibroblasts from FTLD patients with PGRN variants.
• Silenced PGRN in control fibroblasts and assessed parkin and its downstream targets (MFN2, VDAC1).
• Overexpressed or silenced TDP-43 in patient and control fibroblasts to study its effect on parkin and PGRN.

Main Results:

• Parkin was downregulated in fibroblasts from FTLD patients with PGRN variants.
• PGRN silencing in control fibroblasts decreased parkin, MFN2, and VDAC1 levels.
• TDP-43 overexpression rescued parkin levels upon PGRN silencing but not in FTLD fibroblasts; TDP-43 silencing decreased parkin, indicating loss-of-function contribution.

Conclusions:

• Parkin downregulation is a potential common mechanism in FTLD and ALS associated with TDP-43 loss-of-function.
• The PGRN-TDP-43-parkin axis is implicated in the pathogenesis of FTLD.
• Findings suggest therapeutic strategies targeting parkin or TDP-43 may be beneficial for FTLD and ALS.