Receptor sorting through tubular microdomains of Rab7-positive endosomes in Charcot- Marie-Tooth disease 2B
Final Report Abstract
Charcot-Marie-Tooth (CMT) disease is an inherited neuropathy which affects the peripheral nervous system, leading to neurodegeneration. Disease onset occurs generally during adolescence or adulthood and is manifested by muscle weakness, loss of fine motor control and sensation in the extremities. In autosomal dominant Charcot-Marie Tooth type 2B (CMT2B), disease is caused by mutations in the late endosomal Rab7-GTPase. In neurons, Rab7-endosomes are important for the trafficking of growth-factors: Following activation by their respective ligand, growth-factor receptors are endocytosed, subsequently sorted into Rab7-positive endosomes and transported retrogradely to the soma where they regulate gene expression of pro-survival genes. Finally, receptors are degraded through the lysosomal pathway. Intriguingly, recent studies have linked CMT2B to impairments in trafficking of Rab7-positive late endosomes, but how mutations in Rab7-GTPase contribute to growth- factor receptors trafficking in CMT2B remains elusive. I hypothesized that endosomes in CMT2B- Rab7 mutants show perturbed sorting abilities due to disturbed formation of tubular microdomains into which receptors are routed during the sorting/trafficking process. Generally, it is considered that sorting occurs on early endosomes where receptors are sorted into the recycling pathways- either directly back to the plasma membrane or through the trans-Golgi network (TGN). However, I hypothesized that these tubular microdomains on late endosomes also facilitate receptor sorting, potentially into lysosomes. Interestingly, we found that tubular microdomains help avoiding degradation of TrkB receptors and actually facilitates their signaling. Further, we found that not all 4 CMT2B point mutations showed the same phenotype an interesting finding in the light of translational approaches. In addition, we generated a CMT2B-Rab7 iPSC line using CRISPR/Cas. This project allowed us to build an iPSC lab and we now routinely generate sensory and motor neurons.
Publications
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Axon guidance receptors: Endocytosis, trafficking and downstream signaling from endosomes. Progress in Neurobiology, 198, 101916.
Pasterkamp, R.J. & Burk, K.
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Held Up in Traffic—Defects in the Trafficking Machinery in Charcot-Marie-Tooth Disease. Frontiers in Molecular Neuroscience, 14.
Markworth, Ronja; Bähr, Mathias & Burk, Katja
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Tubular microdomains of Rab7-positive endosomes retrieve TrkA, a mechanism disrupted in Charcot–Marie–Tooth disease 2B. Journal of Cell Science, 134(20).
Markworth, Ronja; Dambeck, Vivian; Steinbeck, Lars Malte; Koufali, Angeliki; Bues, Bastian; Dankovich, Tal M.; Wichmann, Carolin & Burk, Katja
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A CRISPR/Cas9 generated knockout-knockin GFP-Rab7-iPSC line to study Charcot-Marie-Tooth 2B (CMT2B) Poster presentation, Amyotrophic Lateral Sclerosis (ALS) and Related Motor Neuron Disease, Gordon Research Conference, Les Diablerets 2023
Katja Burk
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The endocytosis, trafficking, sorting and signaling of neurotrophic receptors. Progress in Molecular Biology and Translational Science, 141-165. Elsevier.
Burk, K.
