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Molecular Networks of Dopaminergic Neurons in Chordates

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New biomarkers and therapy for Parkinson's disease

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, affecting 1–2 % of all individuals above the age of 65. The development of new therapeutics must consider mechanisms of the selective vulnerability of dopaminergic neurons (DNs).


PD affects roughly 2 million people in Europe today. Within the next 50 years, the number is expected to rise to 5 million. No pharmacological treatment is currently available to slow or arrest neurodegeneration. PD is a degenerative disorder of the central nervous system (CNS) with motor symptoms caused by degeneration of A9 DNs in the mesencephalon (also called midbrain). The EU-funded 'Molecular networks of dopaminergic neurons in chordates' (DOPAMINET) aimed to find cis-regulatory elements and transcriptional networks that participate in the coding of DN identity. The DOPAMINET consortium used an interdisciplinary approach to decipher complex networks consisting of protein-coding genes, non-protein–coding genes and cis-regulatory elements within DNs in the brain. This approach was applied across four chordate organisms (human, mouse, zebrafish and ciona intestinalis) to identify core network modules that might play key roles in the biology of these neurons. The entire repertory of channels and receptors of DNs was established. The olfactory receptors are selectively expressed in these cells, suggesting that specific types of odourant-like molecules may act as psychoactive drugs on DNs. The discovery of new isoforms of alpha-synuclein might lead to the development of new drugs to induce or inhibit the synthesis of the c-terminal part of the protein. The repertory of transcription factors (TFs) that are differentially expressed between different types of DNs was established.ċMost importantly, the identification of new gene networks involved in dopaminergic cells' differentiation and maintenance has allowed the creation of cocktails of TFs. These can be used to trigger cell conversion from a dermal fibroblast to a dopamine-releasing neuronal cell. This will have a profound effect in future strategies for restorative therapy of PD. Scientific results were disseminated through presentations at workshops and meetings. Researchers of the consortium published data in 26 papers in high-level journals. Therefore, the discoveries in DOPAMINET led to a better understanding of the disease. The new knowledge has the potential to promote better health and quality of life. Moreover, such initiatives will also reduce the high healthcare costs related to the treatment and care of elderly, cognitively impaired patients.

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