Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration

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 Chun Wong, Albert C. Ludolph, Luc Dupuis

Research output: Contribution to journalArticle

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 showthat a mouse model expressing lowlevels of disease linked-G59S mutant dynactin p150Glued 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.

Original languageEnglish (US)
Article numberddu741
Pages (from-to)2228-2240
Number of pages13
JournalHuman Molecular Genetics
Volume24
Issue number8
DOIs
StatePublished - Apr 15 2015

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Dyneins
Dietary Proteins
Autophagy
Diet Therapy
Mutation
Parkinsonian Disorders
Motor Neurons
Point Mutation
Neurodegenerative Diseases
Proteins
Up-Regulation
Genes
Dynactin Complex

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Wiesner, D., Sinniger, J., Henriques, A., Dieterlé, S., Müller, H. P., Rasche, V., ... Dupuis, L. (2015). Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration. Human Molecular Genetics, 24(8), 2228-2240. [ddu741]. https://doi.org/10.1093/hmg/ddu741

Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration. / Wiesner, Diana; Sinniger, Jérome; Henriques, Alexandre; Dieterlé, Stéphane; Müller, Hans Peter; Rasche, Volker; Ferger, Boris; Dirrig-Grosch, Sylvie; Soylu-Kucharz, Rana; Petersén, Asa; Walther, Paul; Linkus, Birgit; Kassubek, Jan; Wong, Philip Chun; Ludolph, Albert C.; Dupuis, Luc.

In: Human Molecular Genetics, Vol. 24, No. 8, ddu741, 15.04.2015, p. 2228-2240.

Research output: Contribution to journalArticle

Wiesner, D, Sinniger, J, Henriques, A, Dieterlé, S, Müller, HP, Rasche, V, Ferger, B, Dirrig-Grosch, S, Soylu-Kucharz, R, Petersén, A, Walther, P, Linkus, B, Kassubek, J, Wong, PC, Ludolph, AC & Dupuis, L 2015, 'Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration', Human Molecular Genetics, vol. 24, no. 8, ddu741, pp. 2228-2240. https://doi.org/10.1093/hmg/ddu741
Wiesner D, Sinniger J, Henriques A, Dieterlé S, Müller HP, Rasche V et al. Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration. Human Molecular Genetics. 2015 Apr 15;24(8):2228-2240. ddu741. https://doi.org/10.1093/hmg/ddu741
Wiesner, Diana ; Sinniger, Jérome ; Henriques, Alexandre ; Dieterlé, Stéphane ; Müller, Hans Peter ; Rasche, Volker ; Ferger, Boris ; Dirrig-Grosch, Sylvie ; Soylu-Kucharz, Rana ; Petersén, Asa ; Walther, Paul ; Linkus, Birgit ; Kassubek, Jan ; Wong, Philip Chun ; Ludolph, Albert C. ; Dupuis, Luc. / Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 8. pp. 2228-2240.
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