Identification of Anti-prion Compounds as Efficient Inhibitors of Polyglutamine Protein Aggregation in a Zebrafish Model

Schiffer, N. W.; Broadley, Sarah A.; Hirschberger, Thomas; Tavan, Paul; Kretzschmar, Hans A.; Giese, Armin; Haass, Christian; Hartl, F. Ulrich; Schmid, Bettina

doi:10.1074/jbc.m607865200

Cited by 96 publications

(79 citation statements)

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“…1). In recent years, there has been a growing awareness that aggregated forms of huntingtin might inflict the most serious damage to cells before inclusion localization (34)(35)(36)(37). Thus, what conformations are really formed intracellularly and how might they differentially affect cellular processes (Fig.…”

Section: The Conundrum: Understanding Protein Structures Inside Cellsmentioning

confidence: 99%

“…Hsc70) is to prevent proteins from misfolding (44). HSP40 and HSP70 prevent inclusion formation of huntingtin exon 1 and potently inhibit toxicity in several model systems (37)(38)(39)(40). With purified huntingtin exon 1, they intercept smaller oligomers to prevent them forming larger fibrillar oligomers and they change the morphology of the large oligomers that do accumulate (45).…”

Section: The Conundrum: Understanding Protein Structures Inside Cellsmentioning

confidence: 99%

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Protein misfolding inside cells: The case of huntingtin and Huntington's disease

Hatters

2008

IUBMB Life

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SummaryHuntington's disease is one of the several neurodegenerative diseases caused by dominant mutations that expand the number of glutamine codons within an existing poly-glutamine (polyQ) repeat sequence of a gene. An expanded polyQ sequence in the huntingtin gene is known to cause the huntingtin protein to aggregate and form intracellular inclusions as disease progresses. However, the role that polyQ-induced aggregation plays in disease is yet to be fully determined. This review focuses on key questions remaining for how the expanded polyQ sequences affect the aggregation properties of the huntingtin protein and the corresponding effects on cellular machinery. The scope includes the technical challenges that remain for rigorously assessing the effects of aggregation on the cellular machinery.2008 IUBMB IUBMB Life, 60(11): 724-728, 2008

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Section: The Conundrum: Understanding Protein Structures Inside Cellsmentioning

confidence: 99%

Section: The Conundrum: Understanding Protein Structures Inside Cellsmentioning

confidence: 99%

Protein misfolding inside cells: The case of huntingtin and Huntington's disease

Hatters

2008

IUBMB Life

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“…A promising progress for the development of new pharmaceutical agents and for a better understanding of the origin of neurodegenerative diseases is the investigation of small organic compounds that modulate the disease related protein aggregation [1,[13][14][15]. Based on this approach diphenyl-pyrazole (DPP) compounds, in particular anle138b, were identified recently as new pharmaceutical agents for the treatment of prion and Parkinson's diseases, where the aggregation of prion and α-synuclein proteins plays an important role [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates

Deeg

Reiner

Schmidt

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background: Special diphenyl-pyrazole compounds and in particular anle138b were found to reduce the progression of prion and Parkinson's disease in animal models. The therapeutic impact of these compounds was attributed to the modulation of α-synuclein and prion-protein aggregation related to these diseases. Methods: Photophysical and photochemical properties of the diphenyl-pyrazole compounds anle138b, anle186b and sery313b and their interaction with monomeric and aggregated α-synuclein were studied by fluorescence techniques. Results: The fluorescence emission of diphenyl-pyrazole is strongly increased upon incubation with α-synuclein fibrils, while no change in fluorescence emission is found when brought in contact with monomeric α-synuclein. This points to a distinct interaction between diphenyl-pyrazole and the fibrillar structure with a high binding affinity (K d = 190 ± 120 nM) for anle138b. Several α-synuclein proteins form a hydrophobic binding pocket for the diphenyl-pyrazole compound. A UV-induced dehalogenation reaction was observed for anle138b which is modulated by the hydrophobic environment of the fibrils. Conclusion: Fluorescence of the investigated diphenyl-pyrazole compounds strongly increases upon binding to fibrillar α-synuclein structures. Binding at high affinity occurs to hydrophobic pockets in the fibrils. General significance: The observed particular fluorescence properties of the diphenyl-pyrazole molecules open new possibilities for the investigation of the mode of action of these compounds in neurodegenerative diseases. The high binding affinity to aggregates and the strong increase in fluorescence upon binding make the compounds promising fluorescence markers for the analysis of aggregation-dependent epitopes.

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“…These disappointing, but not totally unexpected, findings underscore the need to test in vivo compounds identified ex vivo. Finally, it is worth noting that some compounds inhibiting prion PrP Sc accumulation in infected cells are active in other models of amyloid diseases [125] or against yeast prions [140], suggesting common biochemical pathways and possible common therapeutic targets. Yet, as detailed below, some molecules originally identified for their inhibitory effect in cell culture do also delay disease onset in animals.…”

Section: Infected Cultures For the Identification Of Anti-prion Molecmentioning

confidence: 99%

Cell models of prion infection

Vilette

2007

Vet. Res.

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-Due to recent renewal of interest and concerns in prion diseases, a number of cell systems permissive to prion multiplication have been generated in the last years. These include established cell lines, neuronal stem cells and primary neuronal cultures. While most of these models are permissive to experimental, mouse-adapted strains of prions, the propagation of natural field isolates from sheep scrapie and chronic wasting disease has been recently achieved. These models have improved our knowledge on the molecular and cellular events controlling the conversion of the PrP C protein into abnormal isoforms and on the cell-to-cell spreading of prions. Infected cultured cells will also facilitate investigations on the molecular basis of strain identity and on the mechanisms that lead to neurodegeneration. The ongoing development of new cell models with improved characteristics will certainly be useful for a number of unanswered critical issues in the prion field.

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Identification of Anti-prion Compounds as Efficient Inhibitors of Polyglutamine Protein Aggregation in a Zebrafish Model

Abstract: Several neurodegenerative diseases, including

Cited by 96 publications

References 38 publications

Protein misfolding inside cells: The case of huntingtin and Huntington's disease

Protein misfolding inside cells: The case of huntingtin and Huntington's disease

Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates

Cell models of prion infection

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