Parkinson’s disease (PD) is among the most urgent health and societal challenges of our time. It affects ~1-2% of the population above the age of 65 and its prevalence increases dramatically as the population ages. Current treatments for PD are purely symptomatic and have no impact on disease progression. As a result, patients confront a future of progressive disability, early institutionalization, and premature death. PD has a devastating global socioeconomic impact. In Europe alone, PD affects an estimated 1.2 million people and has a cost of €14 billion per year. Since demographic studies show that patient numbers will continue to grow, effectively doubling by 2040, our failure to make any significant impact to halt or delay disease progression means that PD is now a major challenge to health care and society. 

PD is a phenotypically defined syndrome, diagnosed based on a combination of clinical criteria. The pathological hallmark of PD is the degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNc), in the presence of α-synuclein positive aggregates collectively termed Lewy pathology (LP). Additional neuronal loss and LP occurs across multiple regions of the nervous system, including the olfactory bulb, brainstem nuclei, neocortex, autonomic and enteric nervous systems. This progressive neurodegeneration gives rise to a multitude of progressive motor and non-motor symptoms, including (but not limited to) tremor, rigidity, bradykinesia, autonomic dysfunction, sleep-disorders, neuropsychiatric dysfunction and dementia. Monogenic causes of PD account for <5% of cases in most populations, whereas the vast majority of patients have idiopathic PD (iPD), which is of unknown etiology. While the etiopathogenesis of iPD remains obscure, research has uncovered three major biological processes associated with the disease: mitochondrial dysfunction, aberrant proteostasis, and neuroinflammation. The origin of these phenomena, and to which degree they are cause, effect, or bystanders to disease initiation and progression, is however unknown.