Identification of a factor reducing PFF-induced Lewy Body pathology in dopamine neurons

Safak Er, Piotr Chmielarz, Julia Konovalova, Laura Bandres, Katrina Albert, Mikko Airavaara, Andrii Domanskyi

Forskningsoutput: KonferensbidragPosterPeer review

Sammanfattning

Degeneration of dopaminergic neurons in the substantia nigra (SN) is the reason behind the motor symptoms of the world’s second most common neurodegenerative disorder, Parkinson’s disease (PD). Histopathology of Lewy Bodies (LBs) accompanies the progression of PD. Identifying the exact role of LBs and their main component, α-synuclein, is still one of the biggest quests in the field. Seeding α-synuclein aggregation with preformed fibrils (PFFs) of the protein provides a powerful model which mimics prion-like behaviour and slow progress of its aggregation into LBs. By using PFFs, we have established in vitro phosphoSer129-α-synuclein positive, LB-like aggregates in primary embryonic dopaminergic neurons. Administration of exogenous factor X, pre- or post- PFF treatment are both protective against the formation of LB-like inclusions in dopaminergic neurons. Involvement of specific signalling pathway was supported by knocking down factor X receptor with our in-house established, neuron specific CRISPR-Cas9 system and protective effect of lentiviral overexpression of constitutively active receptor. Pharmacological benefit of factor X was validated in vivo via AAV-mediated overexpression of it in the SN followed by PFF injection into the striatum. Development of novel, pathology-oriented therapies for dopaminergic neurons has a great potential to prevent the progression of PD. Further dissection of the downstream pathways will be beneficial for identification of new targets for prevention of LBs.
Originalspråkengelska
StatusPublicerad - 4 juni 2019
MoE-publikationstypEj behörig
Evenemang5th World Parkinson's Congress - Kyoto Conference Center, Kyoto, Japan
Varaktighet: 4 juni 20197 juni 2019

Konferens

Konferens5th World Parkinson's Congress
Förkortad titelWPC 2019
Land/TerritoriumJapan
OrtKyoto
Period04/06/201907/06/2019

Vetenskapsgrenar

  • 3112 Neurovetenskaper

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