Neuronal self-defence: Identification of mechanisms that protect dopaminergic neuronal health during aging

The aging process is the major risk factor for a wide range of serious and widespread diseases. This affects both the individual's quality of life and the social economy. Understanding the basic mechanisms of cellular ageing is crucial to understanding why we are more prone to disease as we age. One of the processes that has become central to the ageing process is the cell's ability to keep the genetic material intact. Many age-related diseases are linked to defects in DNA repair mechanisms. As we grow older, the capacity of cells to repair DNA damage decreases, which gradually leads to damage to the genome. Numerous studies have shown that accumulation of oxidative DNA damage in brain cells is seen i several neurodegenerative diseases. Dopaminergic cells appear to be extremely sensitive to this type of stress. Using C. elegans models of Parkinson's disease, where dopaminergic nerve cells are lost at a young age, we have found that young animals and cells have great inherent capacity to limit damage and limit the effect of damage on dopaminergic cell function. But there seems to be a point in the life of the animal and cell where there is so much damage that the protective mechanisms help to accelerate degeneration instead of slowing it down. In this project, we will describe what characterizes this transition from beneficial to a pathogenic response that drives aging and age-dependent death of dopaminergic neurons in C. elegans and in cell models made from patients with Parkinson's disease.

Aging and mitochondrial dysfunction are two fundamental processes that contribute to Parkinson´s disease (PD). Although there is growing evidence that DNA damage and repair sit at the intersection of these processes, the mechanisms are unknown. We have developed animal models in which we can follow how DNA repair influences neuronal health over a natural life-course. We have identified a self-defence mechanism that is induced in animals lacking the NTH-1 DNA glycosylase (nth-1) as a consequence of mild mitochondrial dysfunction and that this protects neurons from spontaneous degeneration upon aging. In animals that express mutant alpha-synuclein, however, loss of Base Excision Repair renders the neurons hypersensitive. Thus, Base Excision Repair might modulate the susceptibility to develop PD. The overarching goal of the present proposal is to understand how these neuronal self-defence mechanisms are regulated and to test whether inhibition of Base Excision repair can boost these inborn processes and thereby delay progression of PD . Specifically, we will define the pathways and key regulatory elements protecting dopaminergic neurons in C. elegans. Secondly, we will validate the relevance of this mechanism in an established mouse model of PD, in human neurons in culture and in clinical material.We will develop small molecules to inhibit NTHL1 (the mammalian ortholog of NTH-1) and test whether these activate the neuronal self-defence program. Finally, we will reanalyse existing human exome sequencing data to test whether mitochondrial dysfunction caused by Base Excision Repair defects might define a subclass of PD patients. The proposal builds on strong preliminary data, strong team with unique tools to tackle the main challenges and knowledge needs in the PD field, namely the need to develop intervention strategies to slow down disease progression based on better understanding of disease mechanisms in early phases of the disease.