CELLULAR QUALITY CONTROL AND STRESS RESPONSE PATHWAYS IN NEURODEGENERATION
The major aim of our research activities is to identify key biochemical pathways implicated in neuroprotection and neurotoxicity, which is a prerequisite to identify and develop novel therapeutic strategies for neurodegenerative diseases. Specifically, we are studying various aspects of cellular quality control mechanisms and stress response pathways that maintain neuronal integrity and homeostasis.
E3 UBIQUITIN LIGASES AND UBIQUITIN SIGNALING
Ubiquitination is a highly versatile posttranslational modification regulating fundamental cellular processes, such as protein and organelle turnover, protein trafficking, DNA repair, endocytosis, signaling pathways, and cell cycle progression. Ubiquitination is accomplished by the coordinated action of three enzymes, an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase. Ubiquitin can be attached to substrate proteins as a single moiety or in form of polymeric chains. Reminiscent of a code, the various ubiquitin modifications adopt distinct conformations and serve different cellular functions.
MITOCHONDRIA: KEY ORGANELLES IN ORCHESTRATING CELL DEATH AND VIABILITY
Mitochondria are highly dynamic organelles which fulfill a plethora of functions. In addition to their prominent role in energy metabolism, mitochondria are intimately involved in various cellular processes, such as the regulation of calcium homeostasis, lipid metabolism, assembly of iron sulfur clusters, stress response and cell death pathways. Therefore it is not surprising that mitochondrial dysfunction has emerged as a key factor in several diseases, including neurodegenerative disorders.
Neurons are critically dependent on mitochondrial function and integrity based on specific morphological, biochemical, and physiological features. Consequently, mitochondrial alterations can promote neuronal dysfunction and degeneration. Mitochondrial dysfunction has long been implicated in the etiopathogenesis of PD, based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Our recent studies on the function and dysfunction of PD-associated genes revealed that various aspects of mitochondrial biology appear to be affected, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control. We also observed that common pathological pathways exist in different neurodegenerative diseases that converge on mitochondrial integrity. Therefore, we analyze the regulation of mitochondrial stress response and quality control pathways and how their dysregulation contributes to specific diseases. In this context we are also addressing the role of interorganellar communication in cellular stress response and signaling pathways.