RT Journal Article
SR Electronic
T1 Defined neuronal populations drive fatal phenotype in Leigh Syndrome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 556019
DO 10.1101/556019
A1 Irene Bolea
A1 Alejandro Gella
A1 Elisenda Sanz
A1 Patricia Prada-Dacasa
A1 Fabien Menardy
A1 Pablo Machuca-Márquez
A1 Angela Michelle Bard
A1 Franck Kalume
A1 Albert Quintana
YR 2019
UL http://biorxiv.org/content/early/2019/02/20/556019.abstract
AB Dysfunctions of the mitochondrial energy-generating machinery cause a series of progressive, untreatable and usually fatal diseases collectively known as mitochondrial disease. High energy-requiring organs such as the brain are especially affected, leading to developmental delay, ataxia, respiratory failure, hypotonia, seizures and premature death. While neural affectation is a critical component of the pathology, only discrete neuronal populations are susceptible. However, their molecular identity and their contribution to the disease remain unknown. Mice lacking the mitochondrial Complex I subunit NDUFS4 (Ndufs4KO mice) recapitulate the classical signs of Leigh Syndrome (LS), the most common presentation of mitochondrial disease with predominant CNS affectation. Here, we identify the critical role of two genetically-defined neuronal populations driving the fatal phenotype in Ndufs4KO mice. Selective inactivation of Ndufs4 in Vglut2-expressing glutamatergic neurons causes brainstem inflammation, motor and respiratory deficits, and early death. On the other hand, Ndufs4 deletion in GABAergic neurons leads to basal ganglia inflammation without motor or respiratory involvement, but accompanied by severe refractory epileptic seizures preceding premature death. These results provide novel insight in the cell type-specific contribution to LS pathology and open new avenues to understand the underlying cellular mechanisms of mitochondrial disease.