Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• PMP22 gene mutations cause peripheral neuropathies: duplication leads to Charcot-Marie-Tooth disease type 1A (CMT1A) with hypomyelination, while haplo-insufficiency causes hereditary neuropathy with liability to pressure palsies (HNPP) with focal myelin overgrowth.
• The molecular basis for PMP22's role in regulating myelin growth remains unclear.

Purpose of the Study:

• To investigate the molecular mechanisms underlying PMP22-associated myelin disorders (HNPP and CMT1A).
• To explore the therapeutic potential of targeting the PI3K/Akt/mTOR pathway in HNPP.

Main Methods:

• Analysis of PTEN (a PI3K/Akt/mTOR pathway inhibitor) abundance in rodent models of HNPP and CMT1A.
• In vitro studies using DRG neuron/Schwann cell co-cultures treated with PI3K/Akt/mTOR inhibitors.
• In vivo treatment of HNPP mice with the mTOR inhibitor Rapamycin.

Main Results:

• PTEN abundance correlated with PMP22 levels in peripheral nerves of HNPP and CMT1A models.
• In vitro inhibition of the PI3K/Akt/mTOR pathway reduced hypermyelination in HNPP co-cultures.
• In vivo Rapamycin treatment improved motor function, increased nerve conduction, and reduced pathological features in HNPP mice.
• Schwann cell dedifferentiation in CMT1A was independent of the PI3K/Akt/mTOR pathway, and PTEN ablation did not ameliorate CMT1A.

Conclusions:

• The PI3K/Akt/mTOR pathway is implicated in HNPP pathogenesis and represents a potential therapeutic target.
• PI3K/Akt/mTOR pathway inhibitors may offer a treatment strategy for HNPP-related pressure palsies.
• This pathway is not a viable target for CMT1A, as Schwann cell dedifferentiation in CMT1A is uncoupled from PI3K/Akt/mTOR signaling.