disease (PD) is a chronic neurodegenerative disease that affects motor neuron system. The
decreased activity of the motor system is due to the loss of cells in
Substantia Niagra, a region of the midbrain. The exact cause of cell loss is
poorly understood. However, it involves the build-up of proteins to Lewy bodies
in the neurons. Thus, clearance of this protein aggregates is essential in
healthy individuals, which is mainly mediated
through autophagy. Later people identified different genetic components
involved including PINK1 and PARK2 genes in young onset recessively inherited
PD which are known to be involved in mitophagy, a selective form of autophagy (1,2).
This immediately suggests the possible
involvement of mitochondrial quality control pathways in Parkinson’s disease.
Paraquat is a widely used
herbicide and also one of the reported etiological factors for the development
of Parkinson’s disease. Development of such neurological disease by paraquat is poorly understood. It
undergoes one electron reduction in cells and causes widespread oxidative
stress by generating reactive oxygen species (ROS) in cells. The primary source
of these ROS generated by PQ is in mitochondria. Thus, removal of this damaged
mitochondria is essential to maintain homeostasis in cells. Here we explore the
involvement of a novel regulator of autophagy, caspases-8- and -10-associated
RING proteins 2 (CARP-2 / Rififylin) in paraquat mediated toxicity in mammalian
cells. CARP-2 is one of the only two E3 ligases in the entire human genome that
has both FYVE (Fab1p, YOTB, Vac1p and EEA1) and RING (Really Interesting New
Gene) domains. Using forward genetic screen, Chick et al. recently showed that
overexpression of the gene CARP-2 could provide resistance to stress induced by
paraquat in mouse embryonic fibroblasts (3). Here we hypothesise that CARP-2
protects cells against paraquat stress by facilitating removal of damaged
mitochondria. Even though paraquat resistance in CARP-2 overexpressed cells are reported, the mechanism involved is not
known. Hence, we investigated the role of mitophagy, a well-known process
involved in neurodegenerative diseases and ageing, in CARP-2 mediated
protection against paraquat stress.
1. Valente, E. M. et al. Hereditary Early-Onset Parkinson’s
Disease Caused by Mutations in PINK1. Science. 304, 1158–1160 (2004).
2. Shimizu, N. et al. Mutations in the parkin gene cause
autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).
3. Chick, W. S. et al. Screening for stress-resistance
mutations in the mouse. Front. Genet. 5, 310 (2014).