Mutations in GDAP1 Influence Structure and Function of the Trans-Golgi Network.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Charcot-Marie-Tooth disease (CMT) is a genetically diverse inherited neuropathy.
• The molecular mechanisms underlying most CMT subtypes are poorly understood.
• Understanding CMT pathogenesis is crucial for developing effective therapies.

Purpose of the Study:

• To investigate molecular pathways disrupted by GDAP1 mutations in CMT.
• To establish and utilize yeast and human cell models for CMT-GDAP1 disease.
• To identify potential therapeutic interventions for CMT.

Main Methods:

• Developed yeast and human cell-based models for CMT-GDAP1.
• Analyzed the impact of GDAP1 mutations on protein expression and Golgi structure/function.
• Screened over 1500 existing drugs using the yeast-based CMT-GDAP1 model.

Main Results:

• Certain GDAP1 mutations reduce GDAP1 protein levels, selectively impairing the Golgi apparatus.
• Structural and functional disturbances in the Golgi were observed.
• Identified drugs with both beneficial and detrimental effects on cell phenotypes in the CMT-GDAP1 model.

Conclusions:

• This study is the first to implicate the Golgi apparatus in the pathology of CMT disorders.
• The identified drugs show potential for further translational research in CMT.
• GDAP1 mutations' impact on Golgi function offers new avenues for therapeutic development.