Haruhisa Inoue

An Unfolded Putative Transmembrane Polypeptide, which Can Lead to Endoplasmic Reticulum Stress, Is a Substrate of Parkin

A putative G protein-coupled transmembrane polypeptide, named Pael receptor, was identified as an interacting protein with Parkin, a gene product responsible for autosomal recessive juvenile Parkinsonism (AR-JP). When overexpressed in cells, this receptor tends to become unfolded, insoluble, and ubiquitinated in vivo. The insoluble Pael receptor leads to unfolded protein-induced cell death. Parkin specifically ubiquitinates this receptor in the presence of ubiquitin-conjugating enzymes resident in the endoplasmic reticulum and promotes the degradation of insoluble Pael receptor, resulting in suppression of the cell death induced by Pael receptor overexpression. Moreover, the insoluble form of Pael receptor accumulates in the brains of AR-JP patients. Here, we show that the unfolded Pael receptor is a substrate of Parkin, the accumulation of which may cause selective neuronal death in AR-JP.

Pael-R is accumulated in Lewy bodies of Parkinson's disease.

We examined the distribution of Pael‐R, a newly identified substrate for Parkin, in Parkinsons disease (PD) and multiple system atrophy (MSA). Pael‐R, Parkin, α‐synuclein, and ubiquitin accumulated in Lewy bodies (LBs) and neurites. Pael‐R was localized in the core of LBs. Parkin and α‐synuclein accumulated in the halo, neuronal cell bodies, and processes. These findings potentially suggest the involvement of Pael‐R in LB formation, and protection role of Parkin in Pael‐R‐mediated neurotoxicity in PD. The absence of Pael‐R and Parkin in glial cytoplasmic inclusions (GCIs) in MSA implies a distinct pathway involved in the formation of LBs and GCIs. Ann Neurol 2004

The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model

Mutant copper/zinc superoxide dismutase (SOD1)‐overexpressing transgenic mice, a mouse model for familial amyotrophic lateral sclerosis (ALS), provides an excellent resource for developing novel therapies for ALS. Several observations suggest that mitochondria‐dependent apoptotic signaling, including caspase‐9 activation, may play an important role in mutant SOD1‐related neurodegeneration. To elucidate the role of caspase‐9 in ALS, we examined the effects of an inhibitor of X chromosome‐linked inhibitor of apoptosis (XIAP), a mammalian inhibitor of caspase‐3, ‐7 and ‐9, and p35, a baculoviral broad caspase inhibitor that does not inhibit caspase‐9. When expressed in spinal motor neurons of mutant SOD1 mice using transgenic techniques, XIAP attenuated disease progression without delaying onset. In contrast, p35 delayed onset without slowing disease progression. Moreover, caspase‐9 was activated in spinal motor neurons of human ALS subjects. These data strongly suggest that caspase‐9 plays a crucial role in disease progression of ALS and constitutes a promising therapeutic target.

Pael receptor is involved in dopamine metabolism in the nigrostriatal system

Pael receptor (Pael-R) has been identified as one of the substrates of Parkin, a ubiquitin ligase responsible for autosomal recessive juvenile Parkinsonism (AR-JP). When Parkin is inactivated, unfolded Pael-R accumulates in the endoplasmic reticulum and results in neuronal death by unfolded protein stress, suggesting that Pael-R has an important role in the pathogenesis of AR-JP. Here we report the analyses on Pael-R-deficient (KO) and Pael-R-transgenic (Tg) mice. The striatal dopamine (DA) level of Pael-R KO mice was only 60% of that in normal mice, while in Pael-R Tg mice, striatal 3,4-dihydroxyphenylacetic acid (DOPAC) as well as vesicular DA content increased. Moreover, the nigrostriatal dopaminergic neurons of Pael-R Tg mice are more vulnerable to Parkinsons disease-related neurotoxins while those of Pael-R KO mice are less. These results strongly suggest that the Pael-R signal regulates the amount of DA in the dopaminergic neurons and that excessive Pael-R expression renders dopaminergic neurons susceptible to chronic DA toxicity.

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.