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 and neuromuscular organoids from induced pluripotent stem cells (iPSC). We use CRISPR/Cas9 genome editing in human iPSC 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, and the effects of creatine on neuronal metabolism.
MT-ATP6 in axonal neuropathy
Charcot-Marie-Tooth 1J (ITPR3)
Spinal muscular atrophy Jokela type (CHCHD10)
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 mitochondrial co-chaperones GRPEL1 and GRPEL2 that regulate the protein folding cycle of the mitochondrial chaperone HSP70 in protein import into mitochondrial matrix.
We show that GRPEL1 is essential in mice, and its loss in skeletal muscle results in rapid atrophy and death, with extensive proteotoxic stress responses.
On the contrary, GRPEL2 is not essential in mice, but its loss prevents age- and diet-induced obesity.
We have also discovered a novel small mitochondrial protein NERCLIN, which is transcribed from the GRPEL2 locus through alternative exon usage.