CoEN 4007- Is prion like propagation of alpha synuclein aggregation associated with a ferroptotic cell death

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.

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.

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.
This project will validate our novel hypothesis on the implications of ferroptosis in the
synucleinopathy process (i.e. oligomers formation, aggregation and propagation). We then expect to
demonstrate ferroptosis as a viable therapeutic target as well as identify suitable therapeutic
candidates in protection against synucleinopathy. Clinical, biological and imaging readouts will
identify changes during natural progression associated with ferroptosis and synucleionopathy. As alpha-
syn, iron, glutathione and dopamine are biochemically linked with ferroptosis, combined detection
holds significant potential as a non-invasive biomarker panel of severity. These findings could be
clinically useful in predicting disease trajectory and provide a foundation for anti-ferroptotic drug
administration to subjects with risk factors in the disease. Promising outcomes from our pre-clinical
studies will lead to future clinical trials similar to those led by the consortium. Encouragement for
the manufacturer (ApoPharma) to pursue registration of this compound in such trials (i.e.
Alzheimer: 3D trial, ALS: FAIR-ALS-II), possibly in collaboration with big pharma, will also
encourage the development of other novel iron chelators (i.e. hydroxypyridinones) and ferroptosis
inhibitors (i.e. liproxstatin-1, Ebselen) as next generation therapeutics with a better safety profile.
HCS pharma (Lille, France), the University of Munich and their industrial transfers are currently
developing a range of new ferroptosis inhibitors with potential neuroprotective capabilities that will
be suitable for patients with Parkinson disease.