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

Abstract

Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great genetic heterogeneity. The genes and mutations that underlie this heterogeneity have been extensively characterized by molecular genetics. However, the molecular pathogenesis of the vast majority of CMT subtypes remains terra incognita. Any attempts to perform experimental therapy for CMT disease are limited by a lack of understanding of the pathogenesis at a molecular level. In this study, we aim to identify the molecular pathways that are disturbed by mutations in the gene encoding GDAP1 using both yeast and human cell, based models of CMT-GDAP1 disease. We found that some mutations in GDAP1 led to a reduced expression of the GDAP1 protein and resulted in a selective disruption of the Golgi apparatus. These structural alterations are accompanied by functional disturbances within the Golgi. We screened over 1500 drugs that are available on the market using our yeast-based CMT-GDAP1 model. Drugs were identified that had both positive and negative effects on cell phenotypes. To the best of our knowledge, this study is the first report of the Golgi apparatus playing a role in the pathology of CMT disorders. The drugs we identified, using our yeast-based CMT-GDAP1 model, may be further used in translational research.

GDAP1 Involvement in Mitochondrial Function and Oxidative Stress, Investigated in a Charcot-Marie-Tooth Model of hiPSCs-Derived Motor Neurons

“…In addition, it seems that GDAP1 takes part, also, in regulating Ca 2+ homeostasis, as shown in SH-SY5Y and transfected HeLa cells [23,24]. More recently, GDAP1 interaction with the trans-Golgi network, and its involvement in autophagy and maturation of lysosomes, have been suggested in SH-SY5Y and HeLa models [25,26]. However, the lack of motor neurons of human origin did not allow demonstration of the potential extrapolation of these investigations in the CMT patients.…”

Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1

“…In comparison with many other enzyme superfamilies, GSTs are unique in that sequence conservation appears to be driven by fold stability instead of catalytic features, as reflected in the broad spectrum of GST substrates [ 21 , 22 ]. While the function of GDAP1 is not fully understood at the molecular level, it has been linked to multiple mitochondrial events in neurons [ 23 , 24 ], redox regulation, and signal transduction [ 25 , 26 ].…”

Models for IGHMBP2-associated diseases: an overview and a roadmap for the future

“…A summary of their strengths and weaknesses is presented in Table 2. The S. cerevisiae orthologue of IGHMBP2, Hcs1 (dna HeliCaSe), is an ATP-dependent 5'→3' DNA helicase [61][62][63] belonging to the helicase SF1 Upf1-like family [24,64]. It is truncated (683 aas) and lacks the C-terminal domains when compared to the human protein;…”

“…Yeast has advantages over other more complex models in terms of its low cost, short generation time, simple cultivation and genetic tractability. Yeast is widely used to study human diseases, including neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, Choreaacantocytosis and CMT[54][55][56][57] and has also been used as the basis for high-throughput screens to find genetic or chemical factors that reverse the unfavorable phenotypes of mutations found in patients[58][59][60][61].…”