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Hum Mol Genet. 2015 Jan 15;24(2):525-39. doi: 10.1093/hmg/ddu472. Epub 2014 Sep 12.

Identification and characterization of PKCγ, a kinase associated with SCA14, as an amyloidogenic protein.

Author information

1
Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
2
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
3
Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
4
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
5
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
6
Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan and.
7
Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Science, Hiroshima University, Hiroshima 734-8551, Japan.
8
Biosignal Research Center, Kobe University, Kobe 657-8501, Japan naosaito@kobe-u.ac.jp.

Abstract

Amyloid assemblies are associated with a wide range of human disorders, including Alzheimer's and Parkinson's diseases. Here, we identify protein kinase C (PKC) γ, a serine/threonine kinase mutated in the neurodegenerative disease spinocerebellar ataxia type 14 (SCA14), as a novel amyloidogenic protein with no previously characterized amyloid-prone domains. We found that overexpression of PKCγ in cultured cells, as well as in vitro incubation of PKCγ without heat or chemical denaturants, causes amyloid-like fibril formation of this protein. We also observed that SCA14-associated mutations in PKCγ accelerate the amyloid-like fibril formation both in cultured cells and in vitro. We show that the C1A and kinase domains of PKCγ are involved in its soluble dimer and aggregate formation and that SCA14-associated mutations in the C1 domain cause its misfolding and aggregation. Furthermore, long-term time-lapse imaging indicates that aggregates of mutant PKCγ are highly toxic to neuronal cells. Based on these findings, we propose that PKCγ could form amyloid-like fibrils in physiological and/or pathophysiological conditions such as SCA14. More generally, our results provide novel insights into the mechanism of amyloid-like fibril formation by multi-domain proteins.

PMID:
25217572
DOI:
10.1093/hmg/ddu472
[Indexed for MEDLINE]

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