Neurodegeneration caused by ER stress?-The pathogenetic mechanisms underlying AR-JP.

TAKAHASHI Ryosuke

doi:10.1254/fpj.124.375

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Other Title

小胞体ストレスによる神経変性の分子機構―ＡＲ‐ＪＰのメカニズム―
小胞体ストレスによる神経変性の分子機構--AR-JPのメカニズム
ショウホウタイストレスニヨルシンケイヘンセイノブンシキコウ AR JP ノメカニズム
Neurodegeneration caused by ER stress?
—The pathogenetic mechanisms underlying AR-JP—
―AR-JPのメカニズム―

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Abstract

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.<br>

Journal

Folia Pharmacologica Japonica

Folia Pharmacologica Japonica 124 (6), 375-382, 2004

The Japanese Pharmacological Society

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