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Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease
- Source :
- Tanaka, M, Ishizuka, K, Nekooki-Machida, Y, Endo, R, Takashima, N, Sasaki, H, Komi, Y, Gathercole, A, Huston, E, Ishii, K, Hui, K K W, Kurosawa, M, Kim, S H, Nukina, N, Takimoto, E, Houslay, M D & Sawa, A 2017, ' Aggregation of scaffolding protein DiSC1 dysregulates phosphodiesterase 4 in Huntington's disease ', Journal of Clinical Investigation, vol. 127, no. 4, pp. 1438-1450 . https://doi.org/10.1172/JCI85594
- Publication Year :
- 2017
- Publisher :
- American Society for Clinical Investigation, 2017.
-
Abstract
- Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DiSC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DiSC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DiSC1 led to dysregulation of DiSC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DiSC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DiSC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general.
- Subjects :
- 0301 basic medicine
Scaffold protein
congenital, hereditary, and neonatal diseases and abnormalities
Huntingtin
Transgene
Mice, Transgenic
Nerve Tissue Proteins
Protein aggregation
medicine.disease_cause
Protein Aggregation, Pathological
03 medical and health sciences
DISC1
0302 clinical medicine
Huntington's disease
mental disorders
medicine
Animals
Humans
Genetics
Mutation
Huntingtin Protein
biology
HEK 293 cells
General Medicine
medicine.disease
Cell biology
Cyclic Nucleotide Phosphodiesterases, Type 4
030104 developmental biology
HEK293 Cells
Huntington Disease
biology.protein
Female
030217 neurology & neurosurgery
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Database :
- OpenAIRE
- Journal :
- Tanaka, M, Ishizuka, K, Nekooki-Machida, Y, Endo, R, Takashima, N, Sasaki, H, Komi, Y, Gathercole, A, Huston, E, Ishii, K, Hui, K K W, Kurosawa, M, Kim, S H, Nukina, N, Takimoto, E, Houslay, M D & Sawa, A 2017, ' Aggregation of scaffolding protein DiSC1 dysregulates phosphodiesterase 4 in Huntington's disease ', Journal of Clinical Investigation, vol. 127, no. 4, pp. 1438-1450 . https://doi.org/10.1172/JCI85594
- Accession number :
- edsair.doi.dedup.....2d58968190ea5ce34a01519593affb04