Parkin-mediated reduction of nuclear and soluble TDP-43 reverses behavioral decline in symptomatic mice

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• The function of transactivation DNA-binding protein (TDP)-43 binding to thousands of mRNAs is largely unknown.
• TDP-43 interacts with Park2 mRNA, which encodes the E3 ubiquitin ligase parkin.
• Parkin ubiquitinates TDP-43, promoting its nuclear-to-cytoplasmic translocation.

Purpose of the Study:

• To investigate the therapeutic potential of brain-penetrant tyrosine kinase inhibitors (TKIs) for TDP-43-related pathologies.
• To elucidate the functional relationship between parkin and TDP-43.
• To assess the effects of TKIs on TDP-43 levels and neuronal function.

Main Methods:

• Utilized brain-penetrant TKIs, specifically nilotinib and bosutinib.
• Administered TKIs to mouse models.
• Assessed TDP-43 levels (soluble and insoluble), nuclear localization, and cognitive and motor functions.
• Examined TDP-43 levels in parkin knockout mice.

Main Results:

• TKIs (nilotinib, bosutinib) reduced nuclear TDP-43 levels and mitigated neuronal loss.
• Nilotinib decreased both soluble and insoluble TDP-43, while bosutinib only affected soluble TDP-43.
• TKIs reversed cognitive and motor deficits in affected mice.
• Parkin knockout mice showed elevated endogenous TDP-43, unaffected by TKI treatment, confirming parkin's role in TDP-43 localization.

Conclusions:

• A novel functional link between parkin and TDP-43 was established.
• TKIs demonstrate potential as therapeutic agents for TDP-43 proteinopathies.
• Parkin is essential for regulating TDP-43 sub-cellular distribution.