Mechanisms of selective autophagy in neurodegenerative disease

Neurodegenerative disorders are devastating diseases of the central nervous system representing a major burden to patients, caregivers and society. There are currently no treatment strategies that can halt the degeneration process. It is well known that accumulation of toxic cellular components, such as protein aggregates and damaged mitochondria, are linked to development of such diseases. Thus, it is important to understand how we can prevent buildup of such toxic components or facilitate their removal. We study a process called autophagy, also referred to as self-eating, as autophagy involves capture and delivery of cellular components to the lysosome, the degradation and recycling compartment of the cell. Numerous studies have found that genetic variants affecting autophagy confer increased risk of developing neurodegenerative diseases. In line with this, inhibition of autophagy leads to spontaneous neurodegeneration in several model organisms and more importantly, induction of autophagy seems to delay progression of various neurodegenerative disorders. Thus, therapeutic activation of autophagy holds great promise for treatment of such diseases. The AUTOSELECT project aims to characterize the basal mechanisms involved in clearance of aggregated proteins and damaged mitochondria using cellular and animal models of neurodegenerative disease. We have recently carried out two genetic screens where we have identified several novel regulators of clearance of protein aggregates and mitochondria by autophagy and are currently elucidating their mechanistic role in selective autophagy. Such knowledge will provide new insight into development of neurodegenerative diseases and hopefully lead to new therapeutic approaches for such devastating disorders.

Neurodegenerative disorders are devastating diseases of the central nervous system representing a major burden to patients, caregivers and society. There are currently no treatment strategies that can halt the degeneration process. Numerous studies have found that genetic variants affecting basal cellular processes, such as mitochondrial function and clearance of damaged proteins and organelles by autophagy, confer increased risk of developing neurodegenerative diseases (ND). In line with this, genetic disruption of autophagy leads to spontaneous neurodegeneration in several model organisms and more importantly, induction of autophagy seems to delay progression of various NDs in model organisms. Thus, therapeutic activation of autophagy holds great promise for treatment of NDs. The mechanistic role of autophagy in ND is however far from being understood. The AUTOSELECT project aims to characterize the molecular machinery underlying selective autophagic degradation of aggregated proteins (aggrephagy) and dysfunctional mitochondria (mitophagy) to identify novel regulators of such processes. Promising candidates will be further studied in cellular and animal models of ND available in the lab, directly or through our collaborators. In WP1 we will identify regulators of selective autophagy using high content imaging-based siRNA screens and bioinformatics analysis. In WP2 and WP3 we will use advanced methods, in combination with cellular models of ND, to elucidate the molecular mechanisms underlying the function of regulators identified in WP1. In WP4 we will use genome editing approaches to delete or overexpress our candidate regulators of selective autophagy in already established zebrafish models of ND. We will also collaborate with national and international experts to target our most promising regulators of selective autophagy in induced pluripotent stem cells (iPSCs), Drosophila melanogaster and mouse models of ND.