Journal
ACS CHEMICAL BIOLOGY
Volume 13, Issue 8, Pages 2308-2319Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.8b00466
Keywords
-
Categories
Funding
- Boehringer Ingelheim Fonds
- Studienstiftung des Deutschen Volkes
- Gates Cambridge Scholarships
- St. John's College Benefactors' Scholarship
- UK Biotechnology and Biochemical Sciences Research Council
- Alzheimer's Society, UK [AS-SF-16-003]
- Wellcome Trust
- Frances and Augustus Newman Foundation
- Regione Toscana-FAS Salute-Supremal project
- Marie Sklodowska-Curie Actions-Individual Fellowship
- Sidney Sussex College Cambridge
- Spanish Government-MINECO
- Cambridge Centre for Misfolding Diseases
- UK EPSRC [EP/K039520/1]
Ask authors/readers for more resources
The aggregation of alpha-synuclein, an intrinsically disordered protein that is highly abundant in neurons, is closely associated with the onset and progression of Parkinson's disease. We have shown previously that the aminosterol squalamine can inhibit the lipid induced initiation process in the aggregation of alpha-synuclein, and we report here that the related compound trodusquemine is capable of inhibiting not only this process but also the fibril-dependent secondary pathways in the aggregation reaction. We further demonstrate that trodusquemine can effectively suppress the toxicity of alpha-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of alpha-synuclein inclusions in a Caenorhabditis elegans model of Parkinson's disease, eliminates the related muscle paralysis, and increases lifespan. On the basis of these findings, we show that trodusquemine is able to inhibit multiple events in the aggregation process of alpha-synuclein and hence to provide important information about the link between such events and neurodegeneration, as it is initiated and progresses. Particularly in the light of the previously reported ability of trodusquemine to cross the blood-brain barrier and to promote tissue regeneration, the present results suggest that this compound has the potential to be an important therapeutic candidate for Parkinson's disease and related disorders.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available