The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Transmembrane protein 106B (TMEM106B) is a key genetic risk factor for frontotemporal lobar degeneration (FTLD).
• TMEM106B's precise function, particularly its role in lysosomal dynamics and neuronal morphology, remains largely unknown.
• Lysosomal dysfunction is increasingly implicated in neurodegenerative diseases.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying TMEM106B's function in neurons.
• To investigate the interaction between TMEM106B and its novel binding partner, MAP6.
• To determine how TMEM106B and MAP6 influence lysosomal trafficking and dendritic development.

Main Methods:

• Utilized primary neuronal cultures with TMEM106B knockdown and MAP6 overexpression.
• Employed live imaging techniques to track lysosomal transport dynamics within dendrites.
• Performed rescue experiments by manipulating MAP6 levels and anterograde lysosomal transport.

Main Results:

• TMEM106B knockdown impaired lysosomal trafficking and reduced dendritic arborization.
• Identified microtubule-associated protein 6 (MAP6) as a novel interacting protein with TMEM106B.
• TMEM106B and MAP6 collaboratively regulate the retrograde transport of lysosomes in dendrites, with MAP6 acting as a molecular brake.

Conclusions:

• The TMEM106B/MAP6 interaction is critical for maintaining lysosomal transport balance and dendritic integrity.
• Dysregulation of this interaction, leading to aberrant lysosomal trafficking, may contribute to neurodegeneration in FTLD patients with TMEM106B risk variants.
• Targeting the TMEM106B/MAP6 pathway offers potential therapeutic avenues for FTLD.