Diaminodiphenyl sulfone-induced parkin ameliorates age-dependent dopaminergic neuronal loss.
During normal aging, the number of dopaminergic (DA) neurons in the substantia nigra progressively diminishes, although massive DA neuronal loss is a hallmark sign of Parkinson's disease. Unfortunately, there is little known about the molecular events involved in age-related DA neuronal loss. In this study, we found that (1) the level of parkin was decreased in the cerebellum, brain stem, substantia nigra, and striatum of aged mice, (2) diaminodiphenyl sulfone (DDS) restored the level of parkin, (3) DDS prevented age-dependent DA neuronal loss, and (4) DDS protected SH-SY5Y cells from 1-methyl-4-phenylpyridinium and hydrogen peroxide. Furthermore, pretreatment and/or post-treatment of DDS in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease model attenuated DA neuronal loss and restored motor behavior. DDS transcriptionally activated parkin via protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 signaling and DDS not only failed to induce parkin expression but also failed to rescue SH-SY5Y cells from 1-methyl-4-phenylpyridinium in the absence of ATF4. Herein, we demonstrated for the first time that DDS increased parkin level and served as a neuroprotective agent for age-dependent DA neuronal loss. Thus, DDS may be a potential therapeutic agent for age-related neurodegeneration.
Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon, South Korea; Well Aging Research Center, Daegu Geongbuk Institute of Science and Technology (DGIST), Daegu, South Korea.
Yun-Il
YI
Lee
Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
Hojin
H
Kang
Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon, South Korea.
Young Wan
YW
Ha
Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon, South Korea.
Ki-Young
KY
Chang
Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon, South Korea.
Sung-Chun
SC
Cho
Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon, South Korea.
Sang Ok
SO
Song
Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
Hyein
H
Kim
Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
Areum
A
Jo
Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
Rin
R
Khang
Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
Jeong-Yun
JY
Choi
Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
Yunjong
Y
Lee
Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon, South Korea; Department of New Biology, Daegu Geongbuk Institute of Science and Technology (DGIST), Daegu, South Korea.
Sang Chul
SC
Park
Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea. Electronic address: jshin24@skku.edu.
Joo-Ho
JH
Shin
D051701:Activating Transcription Factor 4 / Q000502:physiology; D000375:Aging; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D003622:Dapsone / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000502:physiology
D051701:Activating Transcription Factor 4; D000893:Anti-Inflammatory Agents; D003622:Dapsone; D018696:Neuroprotective Agents; D044767:Ubiquitin-Protein Ligases; D019892:eIF-2 Kinase; C081452:Atf4 protein, mouse; C111567:parkin protein
Diaminodiphenyl sulfone; Dopaminergic neuron; ER stress; PERK-ATF4 signaling; Parkin; Parkinson's disease