Agents that raise cGMP by activating Protein Kinase G increase 26S proteasome activities, protein ubiquitination, and degradation of misfolded proteins. Therefore, they may be useful in treating neurodegenerative and other diseases caused by an accumulation of misfolded proteins. Mutations in myelin protein zero (MPZ) cause the peripheral neuropathy Charcot Marie Tooth 1B (CMT1B). In peripheral nerves of a mouse model of CMT1B, where the mutant MPZS63del is expressed, proteasome activities are reduced, mutant MPZS63del and polyubiquitinated proteins accumulate, and the Unfolded Protein Response (p-eif2 α) is induced. In HEK293 cells, raising cGMP stimulated ubiquitination and degradation of MPZS63del, but not of MPZWT. Treating S63del mice with the phosphodiesterase 5 inhibitor, sildenafil, to raise cGMP increased proteasome activity in sciatic nerves and reduced the levels of polyubiquitinated proteins, the proteasome reporter ubG76V-GFP, and p-elF2α. Furthermore, sildenafil treatment reduced the number of amyelinated axons, and increased myelin thickness and nerve conduction velocity in sciatic nerves. Thus, agents that raise cGMP, including ones widely used in medicine, may be useful therapies for CMT1B and other proteotoxic diseases.
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