Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain...

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease (PD).
• LRRK2 interacts with microtubules, but its role in microtubule-based axonal transport in PD pathogenesis is unclear.
• Axonal transport deficits are implicated in Parkinson's disease.

Purpose of the Study:

• To investigate whether pathogenic LRRK2 mutations affect microtubule-based axonal transport.
• To elucidate the mechanism by which LRRK2 mutations contribute to Parkinson's disease pathogenesis.
• To identify potential therapeutic interventions targeting LRRK2-mediated axonal transport defects.

Main Methods:

• Assessed LRRK2 association with microtubules in primary neurons and Drosophila models.
• Utilized in vitro assays to examine the effect of microtubule acetylation on LRRK2 binding.
• Employed deacetylase inhibitors (e.g., trichostatin A) and genetic knockdown (HDAC6, Sirt2) to modulate microtubule acetylation.
• Evaluated axonal transport and locomotor behavior in response to LRRK2 mutations and therapeutic interventions.

Main Results:

• Pathogenic LRRK2 mutations (R1441C, Y1699C) preferentially bind deacetylated microtubules.
• Mutant LRRK2 inhibits axonal transport in neurons and causes locomotor deficits in Drosophila.
• Increasing microtubule acetylation prevents mutant LRRK2-microtubule association and restores axonal transport.
• Pharmacological or genetic inhibition of deacetylases rescues axonal transport and locomotor behavior in vivo.

Conclusions:

• Pathogenic LRRK2 mutations impair axonal transport via interaction with deacetylated microtubules, revealing a novel mechanism in Parkinson's disease.
• Microtubule acetylation state is a critical determinant of LRRK2's pathogenic activity.
• Targeting microtubule deacetylation presents a promising therapeutic strategy for Parkinson's disease.