Treatment with diphenyl–pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death

Turriani, Elisa; Lázaro, Diana F.; Ryazanov, Sergey; Leonov, Andrei; Giese, Armin; Schön, Michael P.; Griesinger, Christian; Outeiro, Tiago F.; Arndt‐Jovin, Donna J.; Becker, Dorothea

doi:10.1073/pnas.1700200114

Cited by 34 publications

(49 citation statements)

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“…Until now, anle138b was mostly tested in mouse models 18 , 23 , 50 . In cells, it was tested in melanoma and in H4 cells 51 , 52 . These previous studies, together with our results, show the ability of the compound to decrease aSyn aggregation, both in cells and in vitro, as assessed by RT-QuiC and tau aggregation in cells.…”

Section: Discussionmentioning

confidence: 99%

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Dominguez-Meijide

Vasili²,

König³

et al. 2020

Sci Rep

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Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded α-synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the co-occurrence of both LB and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation and internalization of tau and aSyn. We found that anle138b and fulvic acid decrease aSyn and tau aggregation, that epigallocatechin gallate decreases aSyn aggregation, and that dynasore reduces tau internalization. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Dominguez-Meijide

Vasili²,

König³

et al. 2020

Sci Rep

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“…2), there was no observed effect on cytotoxicity, highlighting that a change if FLT does not necessarily correlate to changes in toxicity. A 7-point concentration response curve (CRC) for A003, A008, A021, and Anle138b (positive control compound, 95,96 ) was performed to determine IC50 for each compound. Both A003 and A021 demonstrated potent inhibition of aSyn induced toxicity with an IC50 of 78nM and 65nM, respectively ( Fig.…”

Section: Secondary Assay: Total Cellular Viabilitymentioning

confidence: 99%

Potent inhibitors of toxic alpha-synuclein oligomers identified via cellular time-resolved FRET biosensor

Braun

Liao

Horvath

et al. 2020

Preprint

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Preventing or reversing the pathological misfolding and self-association of alpha-synuclein (aSyn) can rescue a broad spectrum of pathological cellular insults that manifest in Parkinson's Disease (PD), Dementia with Lewy bodies (DLB), and other alpha-synucleinopathies. We have developed a high-throughput, FRET-based drug discovery platform that combines high-resolution protein structural detection in living cells with an array of functional and biophysical assays to identify novel lead compounds that protect SH-SY5Y cells from aSyn induced cytotoxicity as well as inhibiting seeded aSyn aggregation, even at nanomolar concentrations.Our combination of cellular and cell-free assays allow us to distinguish between direct aSyn binding or indirect mechanisms of action (MOA). We focus on targeting oligomers with the requisite sensitivity to detect subtle protein structural changes that may lead to effective therapeutic discoveries for PD, DLB, and other alphasynucleinopathies. Pilot high-throughput screens (HTS) using our aSyn cellular FRET biosensors has led to the discovery of the first nanomolar-affinity small molecules that disrupt toxic aSyn oligomers in cells and inhibit cell death. Primary neuron assays of aSyn pathology (e.g. phosphorylation of mouse aSyn PFF) show rescue of pathology for two of our tested compounds. Subsequent seeded thioflavin-t (ThioT) aSyn aggregation assays demonstrate these compounds deter or block aSyn fibril assembly. Other hit compounds identified in our HTS are known to modulate oxidative stress, autophagy, and ER stress, providing validation that our biosensor is sensitive to indirect MOA as well. Author contributionsA.R.B. designed and conducted the experiments. E.E.L provided assistance with cell-based assays and western blot experiments. M.C.Y produce and purified recombinant protein. M.H. and K.L. performed primary neuron PFF assays. D.D.T. provided expertise on FRET and HTS, and provided comments and edits to the manuscript. M.E. and R.B. performed statistical model development and analysis on the PFF pathology model. E.E.L. provided comments and edits to the manuscript. A.R.B. and J.N.S. wrote the manuscript. Competing interestsDavid D. Thomas holds equity in and serves as executive officer for Photonic Pharma LLC, a company that owns intellectual property related to technology used in part of this project. These relationships have been reviewed and managed by the University of Minnesota in accordance with its conflict-of-interest polices.

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“…In contrast, however, defective autophagy has also been reported in melanoma as demonstrated by decreased expression of autophagy genes such as LC3 and Beclin1 [ 125 ]. Decrease of autophagy may also lead to impairment of antigen presentation, leading to melanoma immune escape and thereby promoting progression [ 127 ]. Interestingly, a compound targeting alpha-synuclein has recently been shown to kill melanoma cells by dysregulating autophagy [ 127 ].…”

Section: Autophagy Deficits In Pd and Melanomamentioning

confidence: 99%

“…Decrease of autophagy may also lead to impairment of antigen presentation, leading to melanoma immune escape and thereby promoting progression [ 127 ]. Interestingly, a compound targeting alpha-synuclein has recently been shown to kill melanoma cells by dysregulating autophagy [ 127 ]. The precise roles of autophagy in both PD and melanoma remain to be more thoroughly explored, but autophagy deficits may provide mechanistic clues into the correlation between the two diseases.…”

Section: Autophagy Deficits In Pd and Melanomamentioning

confidence: 99%

Parkinson’s Disease and Melanoma: Co-Occurrence and Mechanisms

Bose

Petsko

Eliezer

2018

JPD

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Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, depletion of dopamine in the striatum and the presence of Lewy bodies. Cancer is uncontrolled growth of cells in the body and migration of these cells from their site of origin to other parts of the body. PD and cancer are two opposite diseases, one arising from cell proliferation and the other from cell degeneration. This fundamental difference is consistent with inverse comorbidity between most cancers and neurodegenerative diseases. However, a positive association of PD and melanoma has been reported which has recently become of significant interest. A link between PD and cancer has been supported by many epidemiological studies, most of which show that PD patients have a lower risk of developing most cancers than the general population. However, the mechanisms underlying this epidemiological observation are not known. In this review we focus on epidemiological studies correlating PD and melanoma and the possible mechanisms underlying the co-occurrence of the two diseases. We explore possible explanations for the important observations that more PD patients develop melanoma that would otherwise be expected and vice-versa.

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Treatment with diphenyl–pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death

Cited by 34 publications

References 36 publications

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Potent inhibitors of toxic alpha-synuclein oligomers identified via cellular time-resolved FRET biosensor

Parkinson’s Disease and Melanoma: Co-Occurrence and Mechanisms

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