Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14
| Autor: | Naoko Adachi, Hideyuki Takahashi, Naoaki Saito, Takehiko Ueyama, Takahiro Seki, Norio Sakai, Aoi Nakazono, Daizo Hamada |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Amyloid Detergents Biochemistry Cell Line 03 medical and health sciences chemistry.chemical_compound neurodegenerative disease spinocerebellar ataxia Heat shock protein Cerebellum medicine heat shock protein (HSP) Animals Humans Spinocerebellar Ataxias PKC Protein kinase A Molecular Biology Heat-Shock Proteins Protein Kinase C Hsp40 biology Chemistry protein kinase C (PKC) ataxia Molecular Bases of Disease Cell Biology 70-kilodalton heat shock protein (Hsp70) medicine.disease Hsp90 Hsp70 Cell biology Up-Regulation 030104 developmental biology chaperone protein Protein kinase domain Rifabutin Solubility Celastrol SCA14 heat shock protein 90 (Hsp90) Mutation Spinocerebellar ataxia biology.protein |
| Zdroj: | The Journal of biological chemistry. 293(38) |
| ISSN: | 1083-351X |
| Popis: | Amyloid and amyloid-like protein aggregations are hallmarks of multiple, varied neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. We previously reported that spinocerebellar ataxia type 14 (SCA14), a dominant-inherited neurodegenerative disease that affects cerebellar Purkinje cells, is characterized by the intracellular formation of neurotoxic amyloid-like aggregates of genetic variants of protein kinase Cγ (PKCγ). A number of protein chaperones, including heat shock protein 70 (Hsp70), promote the degradation and/or refolding of misfolded proteins and thereby prevent their aggregation. Here, we report that, in various SCA14-associated, aggregating PKCγ variants, endogenous Hsp70 is incorporated into aggregates and that expression of these PKCγ mutants up-regulates Hsp70 expression. We observed that PKCγ binds Hsp70 and that this interaction is enhanced in the SCA14-associated variants, mediated by the kinase domain that is involved in amyloid-like fibril formation as well as the C2 domain of PKCγ. Pharmacological up-regulation of Hsp70 by the Hsp90 inhibitors celastrol and herbimycin A attenuated the aggregation of mutant PKCγ in primary cultured Purkinje cells. Up-regulation of Hsp70 diminished net PKCγ aggregation by preventing aggregate formation, resulting in decreased levels of apoptotic cell death among primary cultured Purkinje cells expressing the PKCγ variant. Of note, herbimycin A also ameliorated abnormal dendritic development. Extending our in vitro observations, administration of celastrol to mice up-regulated cerebellar Hsp70. Our findings identify heat shock proteins as important endogenous regulators of pathophysiological PKCγ aggregation and point to Hsp90 inhibition as a potential therapeutic strategy in the treatment of SCA14. |
| Databáze: | OpenAIRE |
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