Research

We have identified several new disease genes and variants for neurological diseases by genome-wide next-generation sequencing approaches. We investigate the molecular mechanisms of disease mutations by generating patient-specific motor neurons from reprogrammed skin fibroblasts. We use CRISPR/Cas9 genome editing in human induced pluripotent stem cells to generate disease models and isogenic controls. Currently, we have iPSC-projects on Charcot-Marie-Tooth disease type 1J (ITPR3 gene), spinal muscular atrophy Jokela type (SMAJ, CHCHD10 gene), peripheral neuropathy caused by MT-ATP6 defects, and mitochondrial aminoacyl-tRNA synthetase diseases (AARS, DARS2, SARS2). In addition, we investigate the mechanisms of how metabolism regulates motor neuron differentiation.

• IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta
• Human IP3 receptor triple knockout stem cells remain pluripotent despite altered mitochondrial metabolism

• ITPR3 encoding IP3 receptor type 3 (IP3R3) is a disease gene for dominant Charcot-Marie-Tooth disease   

   

• Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism
• Mitochondrial intermembrane space proteins CHCHD2 or CHCHD10 impact respiration in human motor neurons

• Serum creatine, not neurofilament light, is elevated in CHCHD10-linked spinal muscular atrophy

   

• Threshold of heteroplasmic truncating MT-ATP6 mutation in reprogramming, Notch hyperactivation and motor neuron metabolism

   

• Disease models of mitochondrial aminoacyl-tRNA synthetase defects (review)

• Editing activity by mitochondrial alanyl-tRNA synthetase is essential in mammals

   

• Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

We investigate the consequences of disturbed mitochondrial proteostasis on cell and tissue function, as well as the role of mitochondria in maintaining cellular proteostasis. Recently, we have been specifically interested in the nucleotide exchange factors GRPEL1 and GRPEL2 that regulate the protein folding cycle of the mitochondrial chaperone HSP70 in protein import into mitochondrial matrix.

• Preferential binding of ADP-bound mitochondrial HSP70 to the nucleotide exchange factor GRPEL1 over GRPEL2
• Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure
• Proteotoxic stress responses to loss of GRPEL1, a co-chaperone of mitochondrial HSP70, in skeletal muscle

• Redox regulation of GRPEL2, a co-chaperone of mitochondrial HSP70