[Neurodegeneration caused by ER stress?--the pathogenetic mechanisms underlying AR-JP]

Mutations of the Parkin gene are responsible for autosomal recessive juvenile parkinsonism (AR-JP), the most common cause of early-onset familial Parkinson's disease. Parkin functions as an E3 ubiquitin ligase, thereby promoting ubiquitination and subsequent proteosomal degradation of its substrate(s). AR-JP is, therefore, thought to be caused by accumulation of an unknown toxic protein(s), which would normally be degraded by a molecular machinery involving Parkin. To date, ten different proteins are reported to be substrates of Parkin. Among these, a G protein-coupled orphan receptor called the Pael receptor (Pael-R), which is highly expressed in dopaminergic neurons, attracts particular attention. When over-expressed in cells, the Pael-R protein became improperly folded and insoluble. Excessive accumulation of insoluble Pael-R led to endoplasmic reticulum (ER) stress-induced cell death. Parkin was observed to ubiquitinate the misfolded Pael-R protein, thereby promoting its degradation and suppressing misfolded Pael-R-induced cell death. Moreover, selective dopaminergic neurodegeneration was observed when human Pael-R was ectopically expressed in Drosophila brain, further supporting the idea that Pael-R accumulation plays a major role in AR-JP. In contrast, neither dopaminergic neurodegeneration nor accumulation of any known Parkin substrates was detected in Parkin knockout mice. The role of Pael-R in AR-JP will be discussed based on recent data.