Research suggests that stressed mitochondria call in Parkin and PINK1, which add ubiquitin molecules and phosphate groups to the damaged organelles. The ubiquitin chains then recruit autophagy receptors such as NDP52 and Optineurin, which recruit the full autophagy apparatus.
Adding parkin raised the proportion of cells to nearly 24 percent. Thus, PINK1 can work alone, but parkin adds a big boost. Youle and colleagues suspected that OPTN and NDP52 would work by recruiting LC3, but they were surprised. The mitochondria of double mutants missing both autophagy receptors still collected some LC3, but pentaKOs did not.
LaVoie first tested if dopamine has any effect on parkin in neuronal cell cultures. When the researchers exposed dopaminergic MES cells expressing myc-tagged human parkin to exogenous dopamine (50-100 μM), they found that some of the parkin was rendered insoluble. The catecholamine had a similar, dose-dependent effect on endogenous parkin, reducing the amount of soluble protein by more than ...
From this perch, PINK1’s kinase domain springs into action, phosphorylating ubiquitin, which recruits the ubiquitin ligase Parkin—another PD-linked protein—to tag mitochondria for degradation. While the broad strokes of this process are well-known, precisely how PINK1 remains anchored to the membranes of ailing mitochondria was a puzzle.
The Q311X mutation is a nonsense mutation that produces a C-terminally truncated parkin, just 155 amino acids long. Parkin-Q311X mice (line A) have two copies of the transgene (Tg) integrated in tandem in a bacterial artificial chromosome (BAC), although its integration site is unknown. Notably, as ...
Parkin Flx/Flx mice allow for conditional knockout of the Prkn gene using a Cre-loxP recombination system (Shin et al., 2011). This approach aims to overcome the developmental compensation seen in germline parkin knockouts, enabling adult-onset studies of parkin function in defined tissues (Von ...