Brain最新文献

The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from 2 repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ iPSC-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.

The neuromuscular circuit mechanisms of freezing of gait in Parkinson's disease have received little study. Technological progress enables researchers chronically to sense local field potential activity of the basal ganglia in patients while walking. To study subthalamic activity and the circuit processes of supraspinal contributions to spinal motor integration, we recorded local field potentials, surface EMG of antagonistic leg muscles and gait kinematics in patients while walking and freezing. To evaluate the specificity of our findings, we controlled our findings to internally generated volitional stops. We found specific activation-deactivation abnormalities of oscillatory activity of the subthalamic nucleus both before and during a freeze. Furthermore, we were able to show with synchronization analyses that subthalamo-spinal circuits entrain the spinal motor neurons to a defective timing and activation pattern. The main neuromuscular correlates when turning into freezing were as follows: (i) disturbed reciprocity between antagonistic muscles; (ii) increased co-contraction of the antagonists; (iii) defective activation and time pattern of the gastrocnemius muscle; and (iv) increased subthalamo-muscular coherence with the gastrocnemius muscles before the freeze. Beyond the pathophysiological insights into the supraspinal mechanisms contributing to freezing of gait, our findings have potential to inform the conceptualization of future neurorestorative therapies.

Limb-girdle muscular dystrophy R7 is a rare genetic disease caused by homozygous or compound heterozygous variants in the titin-cap (TCAP) gene that results in the absence of the protein telethonin. The primary pathological features of limb-girdle muscular dystrophy R7 are fiber size variation, nuclear centralization, and abnormal mitochondrial distribution. The mechanisms underlying this disease are unclear, and there is currently no specific treatment for limb-girdle muscular dystrophy R7. This study established a Tcap-deficient mouse model to explore the disease mechanism of mitochondria dislocation and potential therapeutic strategies. We use methods such as proteomics, immunofluorescence, histopathological staining, and western blotting to explore the mechanism of mitochondrial dislocation. Moreover, in the quest for a prospective therapeutic intervention for this disorder, the adeno-associated virus serotype 2/9 was employed to deliver the Tcap gene into the muscles of these mice, facilitating preclinical experimentation. After 2 months and 7 months, the muscular phenotype was evaluated and selected mice were humanely euthanized for subsequent molecular and histological analysis. The phenotype of Tcap-/- mice mimicked that observed in individuals diagnosed with limb-girdle muscular dystrophy R7. This study elucidated the mechanism of mitochondrial dislocation in limb-girdle muscular dystrophy R7. Through our in vitro experiments, we discovered that telethonin aids in preserving the integrity of desmin by preventing truncation at the N-terminus. Additionally, telethonin combined with desmin and colocalized at the Z-disc. Research has shown that the Tcap gene plays a crucial role in controlling the desmin cytoskeleton organization. The absence of telethonin leads to a collapsed desmin cytoskeleton. This causes disorganization of the mitochondrial network, leading to mitochondrial dysfunction. In addition, the study investigated the efficacy of adeno-associated virus (AAV)-mediated Tcap replacement in Tcap-/- mice. By intramuscular delivery of AAV, we observed dramatic improvements in muscle phenotype, muscle pathology, CK levels, muscle magnetic resonance imaging, mitochondrial network organization, and mitochondrial function. The results of this study demonstrated that telethonin deficiency led to desmin cytoskeleton collapse that caused mitochondrial dislocation. AAV-mediated replacement therapy could be a promising safe and efficient treatment option for limb-girdle muscular dystrophy R7. The study highlights the potential of AAV-mediated replacement therapy for specific types of limb-girdle muscular dystrophy.