ABSTRACT
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 (α-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 α-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 α-Syn expression. In contrast, PGRN ameliorated MPP+-induced increase in α-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 α-Syn. The DALGreen assay showed that PGRN ameliorated MPP+-induced decreasing trend of autolysosomes. These results suggest that PGRN participates in α-Syn degradation via acceleration of the autophagy-lysosome pathway and is a potential therapeutic target for PD.
Subject(s)
Neuroblastoma , Parkinson Disease , Animals , Humans , Mice , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects , alpha-Synuclein/metabolism , Disease Models, Animal , Dopaminergic Neurons/metabolism , Lysosomes/metabolism , Mice, Inbred C57BL , Neuroblastoma/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Progranulins/metabolismABSTRACT
VGF nerve growth factor inducible (VGF) is a neuropeptide precursor, which is induced by several neurotrophic factors, including nerve growth factor and brain-derived neurotrophic factor. Clinically, an upregulation of VGF levels has been reported in the cerebrospinal fluid and prefrontal cortex of patients with schizophrenia. In our previous study, mice overexpressing VGF exhibited schizophrenia-related behaviors. In the current study, we characterized the biochemical changes in the brains of VGF-overexpressing mice. Metabolomics analysis of neurotransmitters revealed that glutamic acid and N-acetyl-L-aspartic acid were increased in the striatum of VGF-overexpressing mice. Additionally, the present study revealed that MK-801, which causes the disturbance in glutamic acid metabolism, increased the expression level of VGF-derived peptide (NAPP129, named VGF20), and VGF-overexpressing mice had higher sensitivity to MK-801. These results suggest that VGF may modulate the regulation of glutamic acid levels and the degree of glutamic acid signaling.
Subject(s)
Dizocilpine Maleate , Schizophrenia , Animals , Dizocilpine Maleate/pharmacology , Glutamic Acid , Mice , Phenotype , Prefrontal Cortex/metabolism , Schizophrenia/geneticsABSTRACT
Alzheimer's disease (AD) is characterized by progressive cognitive decline, and the number of affected individuals has increased worldwide. However, there are no effective treatments for AD. Therefore, it is important to prevent the onset of dementia. Oxidative stress and endoplasmic reticulum (ER) stress are increased in the brains of AD patients, and are postulated to induce neuronal cell death and cognitive dysfunction. In this study, Centella asiatica, a traditional Indian medicinal herb, were fractionated and compared for their protective effects against glutamate and tunicamycin damage. Araliadiol was identified as a component from the fraction with the highest activity. Further, murine hippocampal cells (HT22) were damaged by glutamate, an oxidative stress inducer. C. asiatica and araliadiol suppressed cell death and reactive oxygen species production. HT22 cells were also injured by tunicamycin, an ER stress inducer. C. asiatica and araliadiol prevented cell death by mainly inhibiting PERK phosphorylation; additionally, C. asiatica also suppressed the expression levels of GRP94 and BiP. In Y-maze test, oral administration of araliadiol (10 mg/kg/day) for 7 days ameliorated the arm alternation ratio in mice with scopolamine-induced cognitive impairment. These results suggest that C. asiatica and its active component, araliadiol, have neuroprotective effects, which may prevent cognitive dysfunction.
