A Cysteinyl-tRNA Synthetase Mutation Causes Novel Autosomal-Dominant Inheritance of a Parkinsonism/Spinocerebellar-Ataxia Complex

This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes,which has not been depicted by the known neurodegenerative disease.We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia,Parkinsonism,and cognitive function,as well as brain magnetic resonance imaging scans with seven sequences.We searched for co-segregations of abnormal repeat-expansion loci,pathogenic variants in known spinocerebellar ataxiarelated genes,and novel rare mutations via whole-genome sequencing and linkage analysis.A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay.This pedigree presented novel late-onset core characteristics including cerebellar ataxia,Parkinsonism,and pyramidal signs in all nine affected members.Brain magnetic resonance imaging showed cerebellar/pons atrophy,pontine-midline linear hyperintensity,decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus,and hypo-intensities of the cerebellar dentate nuclei,basal ganglia,mesencephalic red nuclei,and substantia nigra,all of which suggested neurodegeneration.Whole-genome sequencing identified a novel pathogenic heterozygous mutation(E795V)in the CARS gene,meanwhile,exhibited none of the known repeat-expansions or point mutations in pathogenic genes.Remarkably,this CARS mutation causes a 20%decrease in aminoacylation activity to charge tRNACys with L-cysteine in protein synthesis compared with that of the wild type.All family members carrying a heterozygous mutation CARS(E795V)had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia.These findings identify novel pathogenesis of Parkinsonismspinocerebellar ataxia and provide insights into its genetic architecture.

Regulation of Cued Fear Expression via Corticotropin-ReleasingFactor Neurons in the Ventral Anteromedial Thalamic Nucleus

The ventral part of the anteromedial thalamic nucleus(AMv)is in a position to convey information to the cortico-hippocampal-amygdalar circuit involved in the processing of fear memory.Corticotropin-releasing-factor(CRF)neurons are closely associated with the regulation of stress and fear.However,few studies have focused on the role of thalamic CRF neurons in fear memory.In the present study,using a conditioned fear paradigm in CRF transgenic mice,we found that the c-Fos protein in the AMv CRF neurons was significantly increased after cued fear expression.Chemogenetic activation of AMv CRF neurons enhanced cued fear expression,whereas inhibition had the opposite effect on the cued fear response.Moreover,chemogenetic manipulation of AMv CRF neurons did not affect fear acquisition or contextual fear expression.In addition,anterograde tracing of projections revealed that AMv CRF neurons project to wide areas of the cerebral cortex and the limbic system.These results uncover a critical role of AMv CRF neurons in the regulation of conditioned fear memory.