– LysMitoPAD

Abnormalities in lysosomes and mitochondria, pivotal organelles regulating cellular homeostasis, are emerging as hallmark features in the pathogenesis of devastating neurodegenerative diseases (NDs) such as Parkinson's disease (PD) and Alzheimer's disease (AD). However, the precise cell-type specific contributions of defective lysosomal and mitochondrial functions to ND pathology at various disease stages remain elusive. This grant proposal aims to bridge this critical knowledge gap by investigating the intricate interplay between lysosomes, mitochondria, and protein aggregation in synucleinopathies and tauopathies. We hypothesize that early dysfunctions of lysosomes and mitochondria drive the accumulation of toxic protein aggregates in ND, exacerbating neurodegeneration. Furthermore, we posit that cell type-specific alterations in lysosomal and mitochondrial dynamics play pivotal roles in disease progression, emphasizing the significance of neuron-glia interactions in preserving neuronal health.
Our multidisciplinary approach integrates state-of-the-art imaging techniques and proteomics, lipidomics and RNA-sequencing, parallel in patient tissue and cellular models to achieve three primary goals:
1. Characterize cell-type specific changes in lysosomal and mitochondrial function in early stages of PD and AD.
2. Elucidate the molecular mechanisms underlying aSyn- and Tau-induced lysosomal and mitochondrial dysfunction.
3. Investigate neuron-glia crosstalk, with a focus on the exchange of lysosomes and mitochondria between cell types and its impact on disease progression.
Our consortium comprises experts in neurobiology, organelle trafficking, protein aggregation pathology, cellular modeling, and bioinformatics, ensuring a comprehensive study of lysosomal and mitochondrial dysfunction in NDs. By unraveling the dynamics, composition, and neuron-glia transfer and of these organelles, we will provide novel insights into common and distinct lysosomal and mitochondrial pathomechanisms in PD, AD, and related tauopathies, with the aim to identify novel therapeutic targets and intervention strategies. In summary, this proposal represents a concerted effort to decipher the complex interplay between lysosomes, mitochondria, and neurodegeneration, with the ultimate goal of developing effective treatments to alleviate the burden of NDs on individuals and society as a whole.