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: Diana Wiesner, Jérome Sinniger, Alexandre Henriques, Stéphane Dieterlé, Hans-Peter Müller, Volker Rasche, Boris Ferger, Sylvie Dirrig-Grosch, Rana Soylu-Kucharz, Asa Petersén, Paul Walther, Birgit Linkus, Jan Kassubek, Philip C Wong, Albert C Ludolph, Luc Dupuis
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 8 Pg. 2228-40 (Apr 15 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25552654 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• DCTN1 protein, human
• Dctn1 protein, mouse
• Dietary Proteins
• Dynactin Complex
• Microtubule-Associated Proteins
• Dyneins

Topics

• Animals
• Autophagy
• Dietary Proteins (metabolism)
• Disease Models, Animal
• Dynactin Complex
• Dyneins (genetics, metabolism)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C3H
• Microtubule-Associated Proteins (genetics, metabolism)
• Motor Activity
• Motor Neurons (metabolism)
• Mutation, Missense
• Nerve Degeneration (diet therapy, genetics, metabolism, physiopathology)