MODIFYPD

Effects of posttranslational modifications of alpha-synuclein on dopaminergic neurodegeneration in a novel viral vector mediated in vivo model of Parkinson’s disease

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 Obiettivo del progetto (Objective)

'One of the major pathological hallmarks of Parkinson´s disease (PD) is the progressive loss of specific dopaminergic projection neurons, especially those located in the substantia nigra pars compacta. The neurodegeneration is accompanied by the presence of cytoplasmic inclusions called Lewy bodies, which invariably contain the α-synuclein (α-syn) protein as a major component. Aggregation of α-syn in the brains of PD patients has attracted much attention also because point mutations in the α-syn gene were found to cause rare dominantly inherited form of PD. Although the precise mechanism of the selective vulnerability of dopaminergic neurons in the midbrain remains unknown, there is increasing evidence that multiple pathogenic factors including impaired handling of cytoplasmic dopamine (DA), elevated levels of reactive oxygen species (ROS) and abnormal phosphorylation of α-syn could cause selective death of these cells via the accumulation of soluble neurotoxic α-syn species. Building on the know how and expertise of the host lab I propose to study 1) the pathogenic interaction of DA/α-syn by genetically increasing cytoplasmic DA levels in the viral vector mediated α-syn overexpression model, which I propose would result in a more pronounced neurodegeneration; 2) the role of ROS by upregulation of the enzyme methionine sulfoxide reductase A (known to prevent oxidative damage by scavenging of ROS). I hypothesize that expression of this enzyme should result in protection of dopaminergic neurons in the α-syn overexpression model; and 3) the consequences of increased Ser 129 phosphorylation of α-syn by overexpressed polo like kinases, which should modify neurotoxicity in the viral vector mediated α-syn overexpression model. These 3 approaches could give important clues for understanding the mechanisms underlying the selective neurodegeneration in PD and thus lead to the development of novel therapeutic strategies in PD.'

Introduzione (Teaser)

The mechanisms underlying Parkinson's disease (PD) are generally poorly understood. A recent EU-funded project investigated aspects of the neurodegeneration associated with the disease.

Descrizione progetto (Article)

PD is a common neurodegenerative disorder affecting about four million people worldwide. It not only alters individuals' quality of life, but also places a high economic burden on society. The disease is characterised by a progressive loss of brain neurons that release the dopamine (DA) hormone. The exact mechanism of this degeneration is unknown, and there is currently no treatment available to prevent or delay disease progression. Researchers explored some of these mechanisms in a project called MODIFYPD.

Previous studies on PD showed that selective neuron death could result from a pathogenic interaction between alpha-synuclein (alpha-syn), a brain protein, and DA. The first aim of MODIFYPD was to test in vivo whether increasing and inhibiting DA synthesis lead to increased and reverse alpha-syn toxicity and degeneration, respectively. Within a mouse model, they found that although DA levels increased the susceptibility to alpha-syn toxicity, it is not the main contributing factor under normal physiological levels.

Another potential cause of neurodegeneration is a chemical alteration (phosphorylation) of an alpha-syn amino acid, Ser129. The MODIFYPD study showed that increased levels of phosphorylated alpha-syn leads to alterations in DA handling. This may indirectly, or in combination with other factors, affect alpha-syn pathology.

These findings have contributed to an enhanced understanding of the mechanisms underlying neurodegeneration in PD. This could assist future researchers in the development of novel therapies for PD.