Journal Article

DZNE-2020-00019

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multiple molecular pathways stimulating macroautophagy protect from alpha-synuclein-induced toxicity in human neurons.

Höllerhage, M. (First author)DZNE* ; Fussi, N.DZNE* ; Rösler, T. W.DZNE* ; Wurst, W.DZNE* ; Behrends, C. ; Höglinger, G. (Last author)DZNE*

2019
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.neuropharm.2019.01.023

Abstract: Pathological aggregates of alpha-synuclein are the common hallmarks of synucleinopathies, including Parkinson's disease. There is currently no disease-modifying therapy approved for neurodegenerative synucleinopathies. The induction of macroautophagy by small compounds may be a strategy to reduce the cellular alpha-synuclein burden and to confer neuroprotection. Therefore, in the present study, we investigated a broad spectrum of druggable molecular signaling pathways reported to induce macroautophagy in human cells and compared their protective efficacy against alpha-synuclein-induced toxicity in cultured human postmitotic dopaminergic neurons. Several compounds affecting different pathways were able to activate macroautophagy. All compounds that activated autophagy also protected against alpha-synuclein-induced toxicity. The compounds with the lowest effective concentrations were PI-103, L-690,330, and NF 449, making them particularly interesting for further investigations, including in vivo models. Our findings demonstrate that activation of macroautophagy, as a neuroprotective approach in synucleinopathies, is accessible to pharmacotherapy. Moreover, pharmacological activation of macroautophagy via diverse signaling pathways is effective to protect human dopaminergic neurons against alpha-synuclein-induced toxicity.

Keyword(s): Autophagy: drug effects (MeSH) ; Benzenesulfonates: pharmacology (MeSH) ; Caspase 3: metabolism (MeSH) ; Caspase 7: metabolism (MeSH) ; Cell Line (MeSH) ; Cell Survival: drug effects (MeSH) ; Diphosphonates: pharmacology (MeSH) ; Dopaminergic Neurons: drug effects (MeSH) ; Furans: pharmacology (MeSH) ; Humans (MeSH) ; Microtubule-Associated Proteins: metabolism (MeSH) ; Neuroprotection (MeSH) ; Parkinson Disease: drug therapy (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Pyridines: pharmacology (MeSH) ; Pyrimidines: pharmacology (MeSH) ; Signal Transduction (MeSH) ; alpha-Synuclein: drug effects (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; 4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate) ; Benzenesulfonates ; Diphosphonates ; Furans ; MAP1LC3B protein, human ; Microtubule-Associated Proteins ; PI103 ; Pyridines ; Pyrimidines ; alpha-Synuclein ; L 690330 ; Caspase 3 ; Caspase 7

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Contributing Institute(s):

1. Translational Neurodegeneration (AG Höglinger 1)
2. Genome Engineering (AG Wurst)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
2. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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