A missense mutation in human INSC causes peripheral neuropathy.

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• The PAR3/INSC/LGN complex is crucial for brain development but its role in the adult peripheral nervous system (PNS) is unclear.
• Axonal Charcot-Marie-Tooth disease (CMT2) is a progressive neurodegenerative disorder affecting peripheral nerves.

Purpose of the Study:

• To investigate the function of the PAR3/INSC/LGN complex in the adult PNS.
• To identify the genetic basis and cellular mechanisms of a novel form of CMT2.

Main Methods:

• Genetic mapping to identify a new CMT2 locus.
• In silico and in vivo modeling of an INSC gene mutation (p.Met70Arg) in Drosophila.
• Cellular analysis of neurodegeneration and tubulin aggregation.
• Assessment of therapeutic efficacy using microtubule-stabilizing agents.

Main Results:

• A missense mutation in the INSC gene was identified as a cause of axonal CMT2.
• The INSC^M70R mutation in Drosophila induced proprioceptive and gait defects, mimicking human CMT2 symptoms.
• Cellular studies revealed tubulin aggregation and neurodegeneration due to PAR3/INSC/LGN dysfunction.
• Microtubule-stabilizing agents ameliorated the observed defects.

Conclusions:

• The PAR3/INSC/LGN complex is vital for the maintenance of the adult PNS.
• INSC mutations can lead to CMT2 through impaired microtubule dynamics and neurodegeneration.
• Targeting microtubule stabilization presents a potential therapeutic strategy for INSC-associated CMT2.