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.
|Tila||Julkaistu - 4 kesäkuuta 2019|
|Tapahtuma||5th World Parkinson's Congress - Kyoto Conference Center, Kyoto, Japani|
Kesto: 4 kesäkuuta 2019 → 7 kesäkuuta 2019
|Konferenssi||5th World Parkinson's Congress|
|Ajanjakso||04/06/2019 → 07/06/2019|
- 3112 Neurotieteet