Genes causative for recessively inherited Parkinson’s disease (PD) include Parkin and Phosphatase and tensin homolog-induced putative kinase 1 (PINK1); rare biallelic mutations in these genes result in definite disease manifestation. On the other hand, heterozygous mutations – occurring in about 2% of the population – may predispose to PD in a dominant manner with highly reduced penetrance. PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and there is new evidence that mitochondrial dysfunction-induced inflammation plays a role in the pathogenesis of Parkin- and PINK1-linked PD: We recently found that patients with heterozygous mutations have a higher heteroplasmic mitochondrial DNA (mtDNA) variant load compared to healthy mutation carriers suggesting that penetrance of Parkin and PINK1 mutations are influenced by low-level mtDNA heteroplasmy. Moreover, we explored the role of inflammation in PINK1- or Parkin-associated PD and detected elevated interleukin 6 levels in Parkin mutation carriers compared to healthy controls. The overarching goal of Project P2 is to define cytokine signatures and to further explore inflammatory pathways in patients with Parkin and PINK1 deficiency. We will determine the levels of inflammatory factors in serum and cerebrospinal fluid samples by performing a cytokine panel analysis from affected vs. unaffected Parkin and PINK1 mutation carriers (Objective 1). Further, we will study microglia activation in Parkin and PINK1 deficiency models by assessing multiple extracellular cytokine analytes and live-cell imaging of microglia under basal conditions and in response to mitochondrial and inflammatory stressors in an iPSC-derived neuron/microglia co-culture (Objective 2). To pinpoint the pathways and factors involved in the protective role of Parkin and PINK1 in neuroinflammation and to explore pathways that may explain the absence of clinical parkinsonism in unaffected heterozygous mutation carriers, we will perform transcriptome profiling of induced pluripotent stem cell (iPSC)-derived neuron/microglia co-cultures by single-cell sequencing. These pathways will then be further validated in pharmacological rescue experiments by treating the cultures with specific agonists and antagonists of selected pathways (Objective 3). We will utilize state-of-the-art technologies, i.e., iPSCs and single-cell RNA sequencing. The project builds on the extensive expertise of the PIs in genetics of movement disorders and the generation and use of neuronal models from iPSCs.
|Effective start/end date
|01.01.16 → …
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):