Impact of Genetic Risk factors and Ageing on Neuronal organellar and lipid homeostasis in Parkinson and Alzheimer’s disease – GRAN’PA
Description: Why do symptoms of most neurodegenerative diseases develop at advanced ages? To answer this question, we need to understand how increasing age affects brain molecular systems. Genetic models for Alzheimer’s (AD) and Parkinson’s disease (PD) link accumulation of toxic aggregates with organellar dyshomeostasis, specifically related to lysosomal and mitochondrial defects. Recent work by this consortium has identified that communication between these organelles fails, involving major affected signaling routes, such as mTORC1 signaling and polyamine transport, intersecting with disturbed lipid metabolism. However, it is unclear how AD/PD genetic risk and protective haplotypes are differentially affected by normal human brain ageing. Hence, the central aim of this proposal is to investigate the effect of aging on selected AD/PD risk loci, when expressed in iPSC-derived versus transdifferentiated neuronal models with retained ageing epigenetic marks. We will validate findings from model systems in brain tissues from a genotyped centenarian brain cohort that is strongly affected by age. This will allow the deconvolution of ageing effects versus those specific for genetic risk alleles.
Funder: Vlaamse regering
Funding type: grant
Funder scheme: BOF - projects
Start date: 2025-10-01
End date: 2029-09-30
Investigators: Willem Annaert, Peter Vangheluwe
Institution: KULeuven
Funded outputs count: 0
Funder award ID: KAC14/25/154
OpenAlex ID: G5101940822