Enhancing Mitofusin/Marf ameliorates neuromuscular dysfunction in Drosophila models of TDP-43 proteinopathies.

No Thumbnail Available
Change log
Khalil, Bilal 
Cabirol-Pol, Marie-Jeanne 
Miguel, Laetitia 
Whitworth, Alexander J 
Lecourtois, Magalie 

Transactive response DNA-binding protein 43 kDa (TDP-43) is considered a major pathological protein in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The precise mechanisms by which TDP-43 dysregulation leads to toxicity in neurons are not fully understood. Using TDP-43-expressing Drosophila, we examined whether mitochondrial dysfunction is a central determinant in TDP-43 pathogenesis. Expression of human wild-type TDP-43 in Drosophila neurons results in abnormally small mitochondria. The mitochondrial fragmentation is correlated with a specific decrease in the mRNA and protein levels of the Drosophila profusion gene mitofusin/marf. Importantly, overexpression of Marf ameliorates defects in spontaneous walking activity and startle-induced climbing response of TDP-43-expressing flies. Partial inactivation of the mitochondrial profission factor, dynamin-related protein 1, also mitigates TDP-43-induced locomotor deficits. Expression of TDP-43 impairs neuromuscular junction transmission upon repetitive stimulation of the giant fiber circuit that controls flight muscles, which is also ameliorated by Marf overexpression. We show here for the first time that enhancing the profusion gene mitofusin/marf is beneficial in an in vivo model of TDP-43 proteinopathies, serving as a potential therapeutic target.

ALS, Dynamin-related protein 1, FTLD, Mitochondria, Mitochondrial dynamics, Animals, DNA-Binding Proteins, Disease Models, Animal, Drosophila, Drosophila Proteins, Dynamins, Gene Expression, Locomotion, Membrane Proteins, Mitochondria, Mitochondrial Dynamics, Molecular Targeted Therapy, Neuromuscular Junction, Neurons, RNA, Messenger, TDP-43 Proteinopathies
Journal Title
Neurobiology of Aging
Conference Name
Journal ISSN
Volume Title
Elsevier BV
All rights reserved
Medical Research Council (MC_UP_1501/1)
Medical Research Council (MC_UU_00015/6)
B. K. had a PhD fellowship from the Ministère de la Recherche. J. C. L. and M. L. are supported by a grant from the Association pour la recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone (ARSLA). M. L. is also supported by a grant from the Région Haute-Normandie.