Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood.

Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

The LisH motif of muskelin is crucial for oligomerization and governs intracellular localization.

Neurons regulate the number of surface receptors by balancing the transport to and from the plasma membrane to adjust their signaling properties. The protein muskelin was recently identified as a key factor guiding the transport of α1 subunit-containing GABAA receptors. Here we present the crystal structure of muskelin, comprising its N-terminal discoidin domain and Lis1-homology (LisH) motif. The molecule crystallized as a dimer with the LisH motif exclusively mediating oligomerization. Our subsequent biochemical analyses confirmed that the LisH motif acts as a dimerization element in muskelin. Together with an intermolecular head-to-tail interaction, the LisH-dependent dimerization is required to assemble a muskelin tetramer. Intriguingly, our cellular studies revealed that the loss of this dimerization results in a complete redistribution of muskelin from the cytoplasm to the nucleus and impairs muskelin's function in GABAA receptor transport. These studies demonstrate that the LisH-dependent dimerization is a crucial factor for muskelin function.