PMID- 37532554
OWN - NLM
STAT- MEDLINE
DCOM- 20230804
LR  - 20230804
IS  - 1347-5215 (Electronic)
IS  - 0918-6158 (Linking)
VI  - 46
IP  - 8
DP  - 2023
TI  - The Involvement of Progranulin for alpha-Synuclein Reduction through Autolysosome 
      Formation.
PG  - 1032-1040
LID - 10.1248/bpb.b22-00711 [doi]
AB  - Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor 
      symptoms and neuropathological features, such as loss of dopaminergic neurons in 
      the substantia nigra pars compacta and accumulation of alpha-synuclein (alpha-Syn). 
      Progranulin (PGRN) is a secreted growth factor that exhibits anti-inflammatory 
      properties and regulates lysosomal function. Although autophagy-lysosome pathway 
      is the main degradative pathway for alpha-Syn, the molecular mechanistic relationship 
      between PD and PGRN remains unclear. In this study, we investigated the role of 
      PGRN in PD pathology. PGRN protein expression in striatum was increased in 
      1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice. 
      Intracerebroventricular (i.c.v.) administration of PGRN ameliorated the decrease 
      in expression of tyrosine hydroxylase, a dopaminergic neuron marker, in 
      MPTP-treated mice. Furthermore, i.c.v. administration of PGRN ameliorated 
      6-hydroxydopamine-induced motor deficits. In SH-SY5Y human neuroblastoma cells, 
      1-methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of MPTP, increased 
      alpha-Syn expression. In contrast, PGRN ameliorated MPP(+)-induced increase in alpha-Syn 
      expression. Although PGRN decreased the levels of autophagy-related proteins 
      Sequestosome-1 (p62) and MAP1LC3 (LC3)-II, PGRN did not influence the 
      phosphorylation of AMP-activated protein kinase and mechanistic target of 
      rapamycin, which are also proteins that regulate autophagy. Immunostaining 
      analysis showed that PGRN ameliorated MPP(+)-induced increase of LC3 puncta, 
      indicator of autophagosome, and co-localization of LC3 and alpha-Syn. The DALGreen 
      assay showed that PGRN ameliorated MPP(+)-induced decreasing trend of 
      autolysosomes. These results suggest that PGRN participates in alpha-Syn degradation 
      via acceleration of the autophagy-lysosome pathway and is a potential therapeutic 
      target for PD.
FAU - Fujimori, Honoka
AU  - Fujimori H
AD  - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu 
      Pharmaceutical University.
FAU - Ohba, Takuya
AU  - Ohba T
AD  - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu 
      Pharmaceutical University.
FAU - Nakamura, Shinsuke
AU  - Nakamura S
AD  - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu 
      Pharmaceutical University.
FAU - Shimazawa, Masamitsu
AU  - Shimazawa M
AD  - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu 
      Pharmaceutical University.
AD  - Lab. of Collaborative Research for Innovative Drug Discovery, Gifu Pharmaceutical 
      University.
FAU - Hara, Hideaki
AU  - Hara H
AD  - Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu 
      Pharmaceutical University.
AD  - Lab. of Collaborative Research for Innovative Drug Discovery, Gifu Pharmaceutical 
      University.
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - Biol Pharm Bull
JT  - Biological & pharmaceutical bulletin
JID - 9311984
RN  - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
RN  - 0 (alpha-Synuclein)
RN  - 0 (Progranulins)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects
MH  - alpha-Synuclein/metabolism
MH  - Disease Models, Animal
MH  - Dopaminergic Neurons/metabolism
MH  - Lysosomes/metabolism
MH  - Mice, Inbred C57BL
MH  - *Neuroblastoma/metabolism
MH  - *Parkinson Disease/drug therapy/metabolism
MH  - Progranulins/metabolism
OTO - NOTNLM
OT  - Parkinson's disease
OT  - autophagy
OT  - lysosome
OT  - progranulin
OT  - alpha-synuclein
EDAT- 2023/08/03 01:06
MHDA- 2023/08/04 06:43
CRDT- 2023/08/02 21:38
PHST- 2023/08/04 06:43 [medline]
PHST- 2023/08/03 01:06 [pubmed]
PHST- 2023/08/02 21:38 [entrez]
AID - 10.1248/bpb.b22-00711 [doi]
PST - ppublish
SO  - Biol Pharm Bull. 2023;46(8):1032-1040. doi: 10.1248/bpb.b22-00711.