Dysfunctions of mitochondria and the autophagy-lysosomal pathway (ALP) take part in the pathologic process of Parkinson’s disease (PD) and are induced by most PD-associated mutations. The Microphthalmia-associated Transcription Factor (MiT) family proteins (MITF, TFEB, TFE3, TFEC) are considered master regulators of autophagy and lysosomal biogenesis and their activity is regulated in response to nutrient availability, therefore connecting cellular metabolism with ALP function.

This project aims at shedding light on a potential mechanistic role of the MiT transcription factor pathway in relation to cellular and mitochondrial health in the etiology of PD and seeks to identify novel targets with the capacity to upregulate the MiT pathway and to increase degradation of aggregates and defective organelles, which may serve as therapeutic approach.

Mechanistic studies will determine how the MiT pathway links mitochondria-lysosomal dysfunctions in the disease cascade of PD in response to metabolic and genetic changes. This will be performed in vitro in SH-SY5Y cells and genetically defined human induced pluripotent stem cells (hiPSC)-derived neurons. In vivo insight will be obtained through internal and external collaborations from C. elegans models and PD-relevant mouse models.

High-throughput screens will aim to discover novel regulators of the MiT pathway, possibly independent of the canonical mTOR pathway. An in vitro CRISPR knockout screen, complemented by genetic screens in C. elegans, will elucidate essential and conserved proteins in the MiT activation pathway. Preclinical validation of identified MiT activators to rescue PD-related phenotypic defects will be carried out in advanced cellular models and in vivo models of PD.

Overall, this project will dissect the link between mitochondrial and ALP dysfunctions in PD and aim to exploit regulation of the MiT pathway as pharmacological target against PD and related neurodegenerative diseases.