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

Abstract

We examined the distribution of Pael-R, a newly identified substrate for Parkin, in Parkinson's disease (PD) and multiple system atrophy (MSA). Pael-R, Parkin, alpha-synuclein, and ubiquitin accumulated in Lewy bodies (LBs) and neurites. Pael-R was localized in the core of LBs. Parkin and alpha-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.

The neuropeptide head activator is a high-affinity ligand for the orphan G-protein-coupled receptor GPR37

“…Similarly, lower levels of GPR37 transcripts by stable expression may have caused less stress for the cells. The fact that insoluble GPR37 was enriched in brains of patients with juvenile Parkinson's disease (Imai et al, 2001) and its presence in Lewy bodies (Murakami et al, 2004) supports the notion that GPR37 misfolding contributes to neuronal cell death . This might be confirmed by the recent finding that GPR37-knockout mice showed altered dopaminergic signalling and were resistant to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which preferentially kills dopaminergic neurons (Marazziti et al, 2004).…”

“…This leads to preferential loss of dopaminergic neurons in the substantia nigra and contributes to neurodegeneration in Parkinson's disease (Yang et al, 2003). Accumulation of GPR37 in Lewy bodies in the brain of patients with Parkinson's disease supports this notion (Murakami et al, 2004).…”

Effects of gender on nigral gene expression and parkinson disease

“…This approach revealed that genes affected by disease but not gender were involved several cellular processes such as transmission of nerve impulse, synaptic transmission, cell-cell signaling, establishment of localization, localization, transport (Fig 3). Among the genes that exhibit gender-independent altered expression in PD are: neuronal beta-catenin, which has been implicated in Alzheimer disease and synaptic plasticity (Fuentealba et al, 2004;Goda, 2002); PAEL-R, a protein accumulated in Lewy bodies (Murakami et al, 2004) and a potential parkin substrate (Nakahara et al, 2003;Yang et al, 2003); kallikrein 6, involved in ASYN degradation (Iwata et al, 2003); and transferrin, which may be related to iron deposition observed in PD brain (Morris et al, 1994).…”

ER stress and neurodegenerative diseases

“…5,33 Pael-R can misfold and form aggregates and the protein is also found in Lewy bodies, suggesting a direct function in PD. 33,35 Parkin suppresses Pael-R-induced toxicity by ubiquitination and degradation of the protein and can protect dopaminergic neurons against various insults. 33 Expression of Parkin can restore proteasome function and promote survival, while loss of function of Parkin causes ER stress with accumulation of cytotoxic fibrils and protein aggregates in cells.…”