Ribosomal associated protein quality control

Maintaining cellular protein homeostasis (proteostasis) is an essential task for all eukaryotes. Proteostasis failure worsens with aging and is considered a cause of and a therapeutic target for age-related diseases including neurodegenerative disorders. The cellular networks regulating proteostasis and the pathogenic events driving proteostasis failure in disease remain poorly understood. Protein translation machinery can be stalled by translational stress when reading the mRNA. The stalling of ribosomes results in the production of truncated polypeptides that can have deleterious effects on cells, and therefore must be eliminated. In eukaryotes, this function is carried out by a dedicated surveillance mechanism known as ribosome-associated protein quality control (RQC). Our research in this part focuses on the role of RQC in various human diseases, especially those related to aging.

Damaged and healthy mitochondria. Image: National Institute on Ageing

mitochondrial quality control

In cells, the dysfunctional mitochondria can be sensed, repaired or removed by a multi-level surveillance system termed mitochondrial quality control (MQC). MQC functions as a hierarchical network of pathways that regulates mitochondrial proteostasis, biogenesis, dynamics and mitophagy to preserve organelle integrity. Two candidate genes of PD, PINK1 and Parkin, have been revealed to play a central role in many different levels of MQC. In our lab, we study how MQC failure contributes to the pathogenesis of various human neurodegenerative diseases. [Example study]

Confocal image of a spinal motor neuron showing stained lipofuscin granules in blue and yellow. McIlwain, et al., (2005). BMC Neurosci. 6, 1, 19.

Batten disease

Batten Disease is an umbrella term of a broad class of rare, autosomal recessive, fatal neurodegenerative disorders, also known as neuronal ceroid lipofuscinoses (NCLs). The major clinical features of Batten disease include progressive visual loss, mental and motor retardation, seizures and premature death. Most cases of Batten disease have been found to have dysfunctional lysosomal functions in patients’ cells. Lysosomes are places where cells digest large biomolecules, complexes, pathogens and cellular organelles to small components for disposal or recycling. Drosophila is an excellent model for conducting both the mechanism study and small-molecule drug screening for human neurological diseases, given its multiple advantages compared to other model systems. In this project, we will systematically analyze the Drosophila Models of Batten Disease.

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