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CoEN 4007- Is prion like propagation of alpha synuclein aggregation associated with a ferroptotic cell death
Note: This project proposes an innovative study that could rapidly lead to neuroprotective treatments against Parkinson's disease, a disorder that affects millions of people within our ageing population. Current available drugs attempt to only treat the disease symptoms not its etiology. We base our project upon recent findings concerning two main features involved in the targeted death of specialized neurons in the brain that secrete a neurotransmitter called dopamine. The first is the abnormal aggregation of a protein called alpha-synuclein that progressively spreads throughout the brain in correlation with the dopaminergic cell death. The second is the involvement of a newly discovered pathway of cell death that we have observed in dopaminergic neurons called ferroptosis. Both phenomena are related with iron; alpha-synuclein is involved in cellular iron balance with its aggregation state modified by the presence of iron, and ferroptosis is an iron dependent process. Thus this project proposes to elucidate how the modifications to alpha-synuclein observed in Parkinson's disease can promote ferroptosis to exacerbate the spreading of neuron death throughout the brain. Outcomes expected from this work are innovative therapeutic strategies based upon recently generated anti-ferroptotic drugs. Technical Summary Cytoplasmic inclusions of aggregated alpha-synuclein (alpha-syn) are the major constituent of Lewy bodies; a pathological hallmark of synucleinopathies including Parkinson's disease (PD). Within certain biological environments alpha-syn self promotes aggregation and neuronal death in a prion-like mode of action. In alpha-syn mutations (i.e. familial PD) and various posttranslational modifications increase the propensity for aggregation, preventing the monomer from functioning as a key regulator of synaptic and endosomal vesicle trafficking. This disrupts dopamine compartmentalization and iron importation, leading to harmful dopamine auto-oxidation and iron accumulation; both prevalent features in PD. Recently, we have shown that a novel regulated necrotic cell death pathway called ferroptosis, defined by iron-dependent lipid peroxidation, is predominant in pro-oxidant models. Our current hypothesis is that alpha-syn dysfunction promotes ferroptosis via iron and dopamine dyshomeostasis, leading to a cellular environment that generates a conformational form of alpha-syn required for prion-like propagation. We aim to demonstrate a pivotal interplay between alpha-syn, iron and ferroptosis using translational studies to genetically and pharmacologically modulate ferroptosis together with clinical longitudinal studies in patients. Outcomes are expected to identify relevant wet (cerebro-spinal fluid) and dry biomarkers (MRI) as well as pave the way to future innovative therapeutic strategies based upon upcoming anti-ferroptotic drugs.
| Grant period | 2018-06-30 - 2021-06-29 |
| Funding body | Medical Research Council |
| Grant number | grant.7748585 |
| Identifier | G:(Dimensions)grant.7748585 |
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Record created 2021-07-01, last modified 2021-09-24