Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology.
Parkinson's disease (PD) is a slowly progressing neurodegenerative disorder with no clear etiology. Pathological hallmarks of the disease include the loss of dopaminergic neurons from the substantia nigra (SN) and the presence of Lewy bodies (LBs) (alpha-synuclein and ubiquitin-positive, eosinophilic, cytoplasmic inclusions) in many of the surviving neurons. Experimental modeling of PD neurodegeneration using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenyl-pyridinium (MPP(+)) has identified changes in gene expression of different endoplasmic reticulum (ER) stress proteins associated with MPTP- and PD-related neurodegeneration. We show that the protein disulfide isomerase (PDI) family member pancreatic protein disulfide isomerase (PDIp), previously considered exclusively expressed in pancreatic tissue, is uniquely upregulated among PDI family members within 24 h following exposure of retinoic acid (RA)-differentiated SH-SY5Y human neuroblastoma cells to either 1 mM MPP(+) or 10 microM of the highly specific proteasome inhibitor lactacystin. RT-PCR confirms PDIp expression in brain of post-mortem human PD subjects and immunohistochemical studies demonstrate PDIp immunoreactivity in LBs. Collectively, these findings suggest that increased PDIp expression in dopaminergic (DA) neurons might contribute to LB formation and neurodegeneration, and that this increased PDIp expression may be the result of proteasome impairment.
Conn
Kelly J
KJ
Department of Veterans Affairs, VA Medical Center, 200 Springs Road, Building 17, Bedford, MA 01730, USA. kconn@bu.edu
Gao
Wenwu
W
McKee
Ann
A
Lan
Michael S
MS
Ullman
M David
MD
Eisenhauer
Patricia B
PB
Fine
Richard E
RE
Wells
John M
JM
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009447:Neuroblastoma; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology
C439978:KCTD13 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; C067713:lactacystin; D014212:Tretinoin; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D000111:Acetylcysteine