Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for α-synuclein fibrils in vitro

Hirohata, Mie; Ono, Kenjiro; Morinaga, Akiyoshi; Yamada, Masahito

doi:10.1016/j.neuropharm.2007.11.010

Cited by 47 publications

(35 citation statements)

References 40 publications

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“…Interestingly, in agreement with our finding that J-domain co-chaperones play a central role in aggregate recognition and processing, a systematic screen in human cell cultures expressing disease-associated polyglutamine proteins (polyQ) revealed that two human DnaJ homologues, DNAJB6b and DNAJB8, are effective suppressors of polyQ aggregation and toxicity (53). This suggests new avenues of therapeutic approaches using chaperone-inducing drugs, such as Hsp90 inhibitors (54) or non-steroidal anti-inflammatory drugs (55). Alternatively, vectors could mediate the specific expression of particular effective J-domain co-chaperones in aging or diseased neurons, thus, targeting more effectively the unfoldase activity of the cytoplasmic Hsp70/Hsp40s to the cytotoxic ␣-Syn oligomers in PD.…”

Section: Discussionsupporting

confidence: 84%

Stable α-Synuclein Oligomers Strongly Inhibit Chaperone Activity of the Hsp70 System by Weak Interactions with J-domain Co-chaperones

Hinault

Cuendet

Mattoo

et al. 2010

Journal of Biological Chemistry

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␣-Synuclein aggregation and accumulation in Lewy bodies are implicated in progressive loss of dopaminergic neurons in Parkinson disease and related disorders. In neurons, the Hsp70s and their Hsp40-like J-domain co-chaperones are the only known components of chaperone network that can use ATP to convert cytotoxic protein aggregates into harmless natively refolded polypeptides. Here we developed a protocol for preparing a homogeneous population of highly stable ␤-sheet enriched toroid-shaped ␣-Syn oligomers with a diameter typical of toxic pore-forming oligomers. These oligomers were partially resistant to in vitro unfolding by the bacterial Hsp70 chaperone system (DnaK, DnaJ, GrpE). Moreover, both bacterial and human Hsp70/Hsp40 unfolding/refolding activities of model chaperone substrates were strongly inhibited by the oligomers but, remarkably, not by unstructured ␣-Syn monomers even in large excess. The oligomers acted as a specific competitive inhibitor of the J-domain co-chaperones, indicating that J-domain co-chaperones may preferably bind to exposed bulky misfolded structures in misfolded proteins and, thus, complement Hsp70s that bind to extended segments. Together, our findings suggest that inhibition of the Hsp70/Hsp40 chaperone system by ␣-Syn oligomers may contribute to the disruption of protein homeostasis in dopaminergic neurons, leading to apoptosis and tissue loss in Parkinson disease and related neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 84%

Stable α-Synuclein Oligomers Strongly Inhibit Chaperone Activity of the Hsp70 System by Weak Interactions with J-domain Co-chaperones

Hinault

Cuendet

Mattoo

et al. 2010

Journal of Biological Chemistry

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“…Moreover, given the pro-inflammatory effects of α-syn, reducing microglial or astroglial activation with non-steroidal anti-inflammatory drugs may also be fruitful area of research 125 . In addition, the considerable biophysical and structural data available for the single conformation of α-syn can be used in targeting the α-syn monomers by decreasing synthesis, increasing clearance, or stabilizing the monomer remains the most viable therapeutic strategy for PD, DLB and related disorders.…”

Section: Perspectives On Therapeutic Targetsmentioning

confidence: 99%

The many faces of α-synuclein: from structure and toxicity to therapeutic target

et al. 2012

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Disorders characterized by α-synuclein (α-syn) accumulation, Lewy body formation and parkinsonism (and in some cases dementia) are collectively known as Lewy body diseases. The molecular mechanism(s) through which α-syn abnormally accumulates and contributes to neurodegeneration in these disorders remains unknown. Here, we provide an overview of current knowledge and prevailing hypotheses regarding the conformational, oligomerization and aggregation states of α-syn and their role in regulating α-syn function in health and disease. Understanding the nature of the various α-syn structures, how they are formed, and their relative contributions to α-syn-mediated toxicity may inform future studies aiming to develop therapeutic prevention and intervention.

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“…Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to have a potent inhibitory effect regarding in-vitro formation of α-syn fibrils in a dose-dependent manner 59 . Given their well-known profile of adverse effects and their wide availability, clinical trials with NSAIDs in MSA patients may be warranted.…”

Section: Potential Therapeutic Targets In Msamentioning

confidence: 99%

Novel therapeutic approaches in multiple system atrophy

Palma

2014

Clin Auton Res

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Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly, progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein–containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprise cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflamatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchimal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review.

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Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for α-synuclein fibrils in vitro

Cited by 47 publications

References 40 publications

Stable α-Synuclein Oligomers Strongly Inhibit Chaperone Activity of the Hsp70 System by Weak Interactions with J-domain Co-chaperones

Stable α-Synuclein Oligomers Strongly Inhibit Chaperone Activity of the Hsp70 System by Weak Interactions with J-domain Co-chaperones

The many faces of α-synuclein: from structure and toxicity to therapeutic target

Novel therapeutic approaches in multiple system atrophy

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