Effects of NogoA in neurodegenerative diseases, especially Parkinson (PD)
Background
A leading area of pharmaceutical research is based on neuroscience therapeutics with vast resources applied to the discovery and development of drugs for disorders in the CNS. According to the World Health Organization (WHO), 8 out of 10 disorders in the 3 highest disability classes are neurological problems and they account for about 12% of deaths worldwide. Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Mitochondrial dynamics, trafficking, turnover and biogenesis play key roles in neurogenesis, neuronal differentiation and neurodegeneration and mitochondrial impairment plays a central role early in the PD pathogenesis; therefore, targeting mitochondria has been proposed for neuroprotection. There is evidence that Nogo-A modulates mitochondrial function in endothelial cells, but this relation has not been studied in neurons.
Aims
Our project aims at studying the role of Nogo-A, a protein of the reticulon family that has been associated with neurite growth and cell death protection of dopaminergic neurons. We will evaluate the expression and the role of Nogo-A in dopaminergic neurons under differentiation, maturation and neurodegeneration and related cellular pathways.
Methods
In our project, mitochondrial function and morphology will be studied in dopaminergic neurons under Nogo-A inhibition using Nogo-A targeting peptides or CRISPR/Cas9 technology. in vitro experimentation using neuron-like cells (wild type and RTN4- knockout), induced pluripotent stem cells (iPSC) derived dopaminergic neurons, LRRK2 (G2019S)-derived dopaminergic neurons, a 3D PD brain model and midbrain-like organoids. Progression of differentiation and/or neurodegeneration will be assessed by state-of-the-art microscopy technologies of stem cell- and neuronal-markers combined with high-content analysis. These analyses will be complemented by the quantitative assessment of key players in cellular pathways (e.g. the ERK/MAP-K, PI3-K/Akt, Wnt/β-catenin) involved in neuronal differentiation and degeneration and mitochondrial function. Finally, targeted-nanotechnology will be used to inhibit Nogo-A in dopaminergic neurons. The uptake of polymeric nanoparticles into dopaminergic neurons will be studied using a novel in vitro microfluidic PD brain model, representing key features of the CNS.
Significance
This project will provide significant and critical insights into the role of Nogo-A during neural differentiation and neurodegeneration and the resulting impacts on the underlying signaling cascades. The findings may offer novel options for early treatment of PD. Findings on drug/peptide delivery in the CNS using neuro-nanotechnology are important regarding safety and efficacy of nano-medicine.
This project is funded by SNSF
