NEURODOPA DEGEN

Elucidating mechanisms of dopaminergic neuronal degeneration using C. elegans and high-throughput genetic approaches

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 Obiettivo del progetto (Objective)

'BACKGROUND: Parkinson’s Disease, characterized by the progressive degeneration of dopaminergic neurons, afflicts millions of people. Yet, no effective therapeutic strategies are available. This work uses Caenorhabditis elegans to study dopaminergic degeneration. C. elegans is a small nematode, highly amenable to genetics and high-throughput approaches, with a simple nervous system that is highly conserved at the level of gene expression and pathology with humans. This study also utilizes a mutant in a Transient Receptor Potential (TRP) channel, trp-4(d), in which dopaminergic neurons properly specify but later on progressively degenerate. OBJECTIVES: 1. Understand the molecular mechanisms of dopaminergic neurodegeneration 2. Identify potential therapeutic targets 3. Uncover novel causes of neuronal cell death STRATEGIES: 1. Using a candidate approach I will investigate which of the known cell death pathways (apoptosis, autophagy, necrosis) mediate trp-4(d) dopaminergic degeneration. 2: I will perform a suppressor screen on trp-4(d) mutants to identify genes that can stop dopaminergic cell death. High-throughput genetic approaches (automated screening and Whole Genome Sequencing) will be employed for mutant isolation and identification. Characterization of the retrieved genes will elucidate molecular mechanisms that can block dopaminergic degeneration. 3. It is conceivable that more genes exist that when mutated have, like trp-4(d), detrimental effect to the survival of DA neurons. I will take an unbiased high-throughput forward genetic screening approach designed to selectively isolate dopaminergic degeneration mutants to reveal novel causes of neuronal cell death. RELEVANCE:The expected outcomes are of high medical significance and relevance to human neurodegenerative conditions. The proposed work, employing state of the art methodology, will not only enhance European competitiveness in disease related research but also contribute to its technological excellence.'

Introduzione (Teaser)

Parkinson's disease, characterised by the progressive degeneration of dopaminergic neurons, affects millions of people. The absence of effective treatments drives scientists to continue research to identify potential therapeutic strategies.

Descrizione progetto (Article)

Dopaminergic neurons, the nerve cells in the brain that produce dopamine, are involved in important biological processes such as movement, motivation and cognition. Their degeneration leads to a pathological condition known as Parkinson's disease. Despite extensive research, current understanding of the molecular mechanisms regulating neuronal cell death is incomplete. This hinders the development of therapeutic or preventative strategies for Parkinson's disease.

The objective of the EU-funded NEURODOPA DEGEN project was to understand the molecular mechanisms of dopaminergic neurodegeneration using a Caenorhabditis elegans model. Combined with advanced genetic methodology, the project resulted in two major breakthroughs related to the development and survival of dopaminergic neurons.

A first important project result was enhanced understanding of the mechanisms responsible for dopaminergic fate specification in C. elegans. The project studied the regulatory mechanisms coordinating expression of the dopamine pathway genes. Genetic screening revealed the transcription factors acting in a cooperative manner. Studies on dopaminergic neurons in the mouse olfactory bulb suggested phylogenetic conservation of dopaminergic regulatory programmes. The findings in C. elegans can be relevant for the mammalian system.

The second important finding was identification of a mutant in which initial normal development of dopaminergic neurons is followed by rapid and progressive degeneration. A single amino acid substitution in a C. elegans transient receptor potential channel was responsible for the degeneration phenotype.

Project findings revealed that not all dopaminergic neurons are equally sensitive to degeneration. This correlates with the selective vulnerability of dopaminergic neurons in the substantia nigra in patients with Parkinson's disease. Additionally, a number of 'suppressor' mutations, partially or fully protecting dopaminergic neurons from a specific degeneration pattern, were identified.

Further studies on these mutants will advance understanding of the calcium-handling mechanisms and dopaminergic neuroprotection in general.