Leigh Syndrome
https://www.jci.org/articles/view/187571
Leigh Syndrome (LS) is a rare neurological disorder caused by defects in mitochondria, the cell’s energy supplier. Many individuals with LS experience treatment-resistant seizures, but the mechanisms behind this mitochondrial epilepsy remain poorly understood. In this study, researchers used a mouse model lacking a key mitochondrial protein, NDUFS4, which closely mimics human LS. They found that this mitochondrial dysfunction particularly damaged a subset of inhibitory neurons that produce a protein called LHX6 within a brain region known as the external globus pallidus (GPe). The loss of these cells disrupted the balance between excitation and inhibition in brain circuits, ultimately leading to increased seizure susceptibility. Notably, restoring NDUFS4 in the GPe using a gene therapy approach prevented seizures and extended the lifespan of the treated mice. The study also identified the subthalamic nucleus (STN) as an important contributor to the propagation of seizures in the context of mitochondrial dysfunction. When researchers silenced excitatory neurons in the STN, the frequency and severity of seizures were reduced. Together, the findings highlighted the role of the GPe-STN circuit in the development of epilepsy in mitochondrial disorders. Data further suggested that restoring mitochondrial function in the GPe or reducing STN hyperactivity may represent promising novel approaches to tackle mitochondrial epilepsy.