title: Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration.
abstract: Mutations in components of the molecular motor dynein/dynactin lead to neurodegenerative diseases of the motor system or atypical parkinsonism. These mutations are associated with prominent accumulation of vesicles involved in autophagy and lysosomal pathways, and with protein inclusions. Whether alleviating these defects would affect motor symptoms remain unknown. Here, we show that a mouse model expressing low levels of disease linked-G59S mutant dynactin p150(Glued) develops motor dysfunction >8 months before loss of motor neurons or dopaminergic degeneration is observed. Abnormal accumulation of autophagosomes and protein inclusions were efficiently corrected by lowering dietary protein content, and this was associated with transcriptional upregulations of key players in autophagy. Most importantly this dietary modification partially rescued overall neurological symptoms in these mice after onset. Similar observations were made in another mouse strain carrying a point mutation in the dynein heavy chain gene. Collectively, our data suggest that stimulating the autophagy/lysosomal system through appropriate nutritional intervention has significant beneficial effects on motor symptoms of dynein/dynactin diseases even after symptom onset.
authors.affiliation: Department of Neurology.
authors.forename: Diana
authors.initials: D
authors.lastname: Wiesner
authors.affiliation: Inserm U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg F-67085, France, Université de Strasbourg, Fédération de Médecine Translationnelle (FMTS), UMRS1118, Strasbourg F-67085, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Sinniger
authors.affiliation: Inserm U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg F-67085, France, Université de Strasbourg, Fédération de Médecine Translationnelle (FMTS), UMRS1118, Strasbourg F-67085, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Henriques
authors.affiliation: Inserm U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg F-67085, France, Université de Strasbourg, Fédération de Médecine Translationnelle (FMTS), UMRS1118, Strasbourg F-67085, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dieterlé
authors.affiliation: Department of Neurology.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Müller
authors.affiliation: Department of Neurology.
authors.forename: Volker
authors.initials: V
authors.lastname: Rasche
authors.affiliation: CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Ferger
authors.affiliation: Inserm U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg F-67085, France, Université de Strasbourg, Fédération de Médecine Translationnelle (FMTS), UMRS1118, Strasbourg F-67085, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dirrig-Grosch
authors.affiliation: Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, 22184 Lund, Sweden and.
authors.forename: Rana
authors.initials: R
authors.lastname: Soylu-Kucharz
authors.affiliation: Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, 22184 Lund, Sweden and.
authors.forename: Asa
authors.initials: A
authors.lastname: Petersén
authors.affiliation: Central Facility for Electron Microscopy, Ulm University, 89081 Ulm, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.affiliation: Department of Neurology.
authors.forename: Birgit
authors.initials: B
authors.lastname: Linkus
authors.affiliation: Department of Neurology.
authors.forename: Jan
authors.initials: J
authors.lastname: Kassubek
authors.affiliation: Department of Pathology and Neuroscience and Division of Neuropathology, The Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Department of Neurology.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Inserm U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg F-67085, France, Université de Strasbourg, Fédération de Médecine Translationnelle (FMTS), UMRS1118, Strasbourg F-67085, France, ldupuis@unistra.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
mesh_terms: D000818:Animals; D001343:Autophagy; D004044:Dietary Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D000072159:Dynactin Complex; D004398:Dyneins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C000606360:DCTN1 protein, human; C000606364:Dctn1 protein, mouse; D004044:Dietary Proteins; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D004398:Dyneins