Congo Red, an Amyloid-Inhibiting Compound, Alleviates Various Types of Cellular Dysfunction Triggered by Mutant Protein Kinase Cγ That Causes Spinocerebellar Ataxia Type 14 (SCA14) by Inhibiting Oligomerization and Aggregation

Seki, Takahiro; Takahashi, Hideyuki; Yamamoto, Kazuhiro; Ogawa, Kota; Onji, Tomoya; Adachi, Naoko; Tanaka, Shigeru; Hide, Izumi; Saito, Naoaki; Sakai, Norio

doi:10.1254/jphs.10170fp

Cited by 13 publications

(10 citation statements)

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“…Although Congo red could be an effective treatment for dysfunctions that are triggered by mutant γPKC, it is not an ideal compound for the treatment of SCA14 because of its low permeability to the BBB, the carcinogenic activity of its metabolites, and its toxicity (33). We confirmed that a higher concentration of Congo red induced an aberrant morphology of PC dendrites (32). Because there are several derivatives of Congo red that have an improved ability to cross the BBB (33), these derivatives may be more suitable for SCA14 treatment than Congo red.…”

Section: Exploration Of Novel Therapeutics Against Dysfunctions Triggsupporting

confidence: 65%

“…We also examined the effects of Congo red (32), which is widely used as an amyloid dye and has the ability to inhibit oligomerization and fibrillization with an amyloid structure (33). Similar to trehalose, Congo red inhibited aggregation and oligomerization of mutant γPKC, thereby preventing the induction of apoptosis and alleviating aberrant morphology of PCs.…”

Section: Exploration Of Novel Therapeutics Against Dysfunctions Triggmentioning

confidence: 99%

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Elucidation of the Molecular Mechanism and Exploration of Novel Therapeutics for Spinocerebellar Ataxia Caused by Mutant Protein Kinase Cγ

et al. 2011

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Abstract. Spinocerebellar ataxia (SCA) is an inherited neurodegenerative disorder that is characterized by cerebellar atrophy and progressive ataxia and is classified into 31 types by the genetic locus. Recently, missense mutations of PRKCG genes that code protein kinase Cγ (γPKC) have been identified as a causal gene of SCA14. To explore the molecular mechanism of SCA14 pathogenesis, we investigated how mutant γPKC causes the neurodegeneration of cerebellar Purkinje cells (PCs) by expressing mutant γPKC-GFP in cell lines and primary cultured PCs. Mutant γPKC was susceptible to aggregation in the cytoplasm, which led to an impairment of the ubiquitinproteasome system and apoptosis. Furthermore, mutant γPKC induced improper dendritic development of cultured PCs in an aggregation-independent manner. Stimulation-induced translocation of mutant γPKC in PC dendrites was prominently attenuated by the reduced mobility of oligomerized mutant γPKC, which resulted in attenuated signal transduction and the improper morphology of PC dendrites. These findings suggested that the oligomerization and aggregation of mutant γPKC caused improper dendritic development and apoptosis of PCs, which led to cerebellar dysfunction and SCA14 pathogenesis. We screened the chemicals that improved these cellular dysfunctions and identified several compounds, including trehalose and Congo red, which could be novel therapeutics for SCA14.

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Section: Exploration Of Novel Therapeutics Against Dysfunctions Triggsupporting

confidence: 65%

Section: Exploration Of Novel Therapeutics Against Dysfunctions Triggmentioning

confidence: 99%

Elucidation of the Molecular Mechanism and Exploration of Novel Therapeutics for Spinocerebellar Ataxia Caused by Mutant Protein Kinase Cγ

et al. 2011

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“…It is also possible that the point mutations do affect biological activity differently, but this may not be the crucial aspect for the development of the disease, which could e.g. be promoted by protein aggregation [14, 15] of other mechanisms [29]. Taken together, our findings show, that biological activity of PKCγ is affected in opposing ways for catalytic versus regulatory domain mutations but the reasons for the similar neuropathological changes in both conditions still remain elusive.…”

Section: Discussionmentioning

confidence: 99%

Increased biological activity of protein Kinase C gamma is not required in Spinocerebellar ataxia 14

Shimobayashi

Kapfhammer

2017

Mol Brain

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Spinocerebellar ataxia (SCA) is an autosomal dominant neurodegenerative disorder characterized by slowly progressive cerebellar dysfunction. Currently, 42 SCA types are known, some of which are caused by CAG repeat expansions, but others are caused by point mutations or deletions. Spinocerebellar ataxia type 14 (SCA14) is caused by missense mutations or deletions in the PRKCG gene, coding for protein kinase C gamma (PKCγ). It is still not well understood how these mutations eventually cause Purkinje cell dysfunction and death. Because PKCγ is a well characterized signaling protein highly expressed in Purkinje cells SCA14 offers the chance to better understand the pathogenesis of Purkinje cell dysfunction and death. Altered biological activity of PKCγ would be the simplest explanation for the disease phenotype. There are indeed indications that the enzymatic activity of mutated PKCγ proteins could be changed. Many mutations found in SCA14 families are located in the regulatory C1B and C1A domain, while a few mutations are also found in the C2 and in the catalytic C3 and C4 domains. For many of these mutations an increased enzymatic activity could be demonstrated in cell-based assays, but it remains unclear whether there is indeed an altered biological activity of the mutated PKCγ proteins within living Purkinje cells. In this study we used the dendritic morphology of developing Purkinje cells to detect increased biological activity of PKCγ after expression of different mutated PKCγ proteins. Our results indicate that two out of three known mutations in the catalytic domain of PKCγ did indeed show increased biological activity. On the other hand, none of the five tested mutations located in the regulatory C1 or the C2 domain showed an increased biological activity. Our findings indicate that SCA14 mutations located in different domains of the PRKCG gene cause SCA14 by different mechanisms and that an increased constitutive activity of PKCγ may be one, but cannot be the only mechanism to cause disease in SCA14.

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“…Interestingly, Yamamoto et al (2010) reported that stimulation of autophagy provoked by treatment with rapamycin can promote the degradation of mutant PKCγ enzymes, while normal kinases are not affected. Moreover, aggregate formation and the cytotoxicity induced by mutant γPKCs has been reported to be inhibited in SH-SY5Y cells by congo red, a dye known to inhibit amyloid oligomers and fibril formation of misfolded proteins (Seki et al, 2010). Various groups, including ours, have shown that EGCG and resveratrol can stimulate autophagy in various types of cells, including macrophages (Li et al, 2011; Kim et al, 2013; Pallauf and Rimbach, 2013), and prevent the formation of Aβ oligomers and fibrils (Bastianetto et al, 2006, 2008; Cheng et al, 2013), suggesting that polyphenols may be beneficial in the treatment of SCA14 patients.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of resveratrol and epigallocatechin gallate polyphenols are mediated by the activation of protein kinase C gamma

Ménard

Bastianetto

Quirion

2013

Front. Cell. Neurosci.

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Polyphenols such as epigallocatechin gallate (EGCG) and resveratrol have received a great deal of attention because they may contribute to the purported neuroprotective action of the regular consumption of green tea and red wine. Many studies, including those published by our group, suggest that this protective action includes their abilities to prevent the neurotoxic effects of beta-amyloid, a protein whose accumulation likely plays a pivotal role in Alzheimer's disease. Moreover, the scavenging activities of polyphenols on reactive oxygen species and their inhibitory action of cyclooxygenase likely explain, at least in part, their antioxidant and anti-inflammatory activities. Besides these well-documented properties, the modulatory action of these polyphenols on intracellular signaling pathways related to cell death/survival (e.g., protein kinase C, PKC) has yet to be investigated in detail. Using rat hippocampal neuronal cells, we aimed to investigate here the effects of EGCG and resveratrol on cell death induced by GF 109203X, a selective inhibitor of PKC. The MTT/resazurin and spectrin assays indicated that EGCG and resveratrol protected against GF 109203X-induced cell death and cytoskeleton degeneration, with a maximal effect at 1 and 3 μM, respectively. Moreover, immunofluorescence data revealed that cells treated with these polyphenols increased PKC gamma (γ) activation and promoted neuronal interconnections. Finally, we found that the protective effects of both polyphenols on the cytoskeleton and synaptic plasticity were mediated by the PKCγ subunit. Taken together, the results suggest that PKC, and more specifically its γ subunit, plays a critical role in the protective action of EGCG and resveratrol on neuronal integrity.

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Congo Red, an Amyloid-Inhibiting Compound, Alleviates Various Types of Cellular Dysfunction Triggered by Mutant Protein Kinase Cγ That Causes Spinocerebellar Ataxia Type 14 (SCA14) by Inhibiting Oligomerization and Aggregation

Cited by 13 publications

References 50 publications

Elucidation of the Molecular Mechanism and Exploration of Novel Therapeutics for Spinocerebellar Ataxia Caused by Mutant Protein Kinase Cγ

Elucidation of the Molecular Mechanism and Exploration of Novel Therapeutics for Spinocerebellar Ataxia Caused by Mutant Protein Kinase Cγ

Increased biological activity of protein Kinase C gamma is not required in Spinocerebellar ataxia 14

Neuroprotective effects of resveratrol and epigallocatechin gallate polyphenols are mediated by the activation of protein kinase C gamma

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