ABSTRACT
Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world. Apart from motor deficits, PD reduces patient's quality of life through sleep disturbances, cognitive impairment and emotional disorders. However, it's unclear whether bad life habits such as stay up late exacerbate the patient's cognition and emotional disorders. Thus we investigated the consequences of sleep deprivation (SD) on memory and emotions using a rotenone-based zebrafish model of PD. Behavioral assays, using locomotor activity assay, showed that rotenone treated zebrafish exhibited PD-like symptoms, whereas sleep deprivation didn't exacerbate the progression of them. The object discrimination task exhibited that the short-term cognitive deficits of rotenone group are more serious than the sham group after SD. Light-dark box test showed that rotenone treated fish are more dysphoric than the sham fish after SD. Dopamine and DOPAC significantly reduced in rotenone treated fish compared with the sham fish. However, this DOPAC reduction recovered after SD. The expression of D2 and D3 in rotenone treated zebrafish elevated compared with sham group and SD group. However, the rotenone treated zebrafish manifested a decrease level of D2 and D3 after SD. D1 did not show any significantly changes among the four groups. Our findings suggest that zebrafish treated with rotenone may have a more severe damage of memory and emotional function after SD, which may be related to the changes in the DA systems.
Subject(s)
Emotions/physiology , Memory/physiology , Sleep Deprivation/physiopathology , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Cognition/physiology , Disease Models, Animal , Dopamine/metabolism , Male , Motor Activity , Parkinson Disease/physiopathology , Rotenone/pharmacology , Sleep Deprivation/metabolism , Zebrafish/metabolism , Zebrafish/physiologyABSTRACT
Olfactory impairment is an early feature of patients with Parkinson's disease (PD). Retrospective epidemiological studies reported lower scores on the University of Pennsylvania Smell Identification Test (UPSIT) in non-smokers than smokers with PD and showed an inverse correlation between susceptibility to PD and a person's history of smoking. But the mechanisms by which cigarettes affect olfaction in PD are not fully understood. So we investigated the effect of nicotine on the olfactory function in 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP)-treated mice. We observed that nicotine improved locomotor activity and protection against dopaminergic neuron loss in the midbrain in MPTP-treated mice. Compared to controls, MPTP-treated mice showed a deficit of odor discrimination and odor detection, which were alleviated by nicotine treatment. But no significant changes were found in olfactory memory in MPTP-treated mice. Moreover, we detected a marked decrease of Choline acetyltransferase (ChAT) expression in the olfactory bulb (OB) in MPTP-treated mice, which was also attenuated by nicotine administration. In addition, nicotine ameliorated the loss of cholinergic neurons and dopaminergic innervation in the horizontal limb of the diagonal band (HDB), which is the primary origin of cholinergic input to the OB. Our results suggested that nicotine could improve the olfactory impairment by protecting cholinergic systems in the OB of MPTP-treated mice. And nicotine protection of cholinergic systems in the OB is relevant to attenuating dopaminergic neuron loss in the midbrain and HDB.
Subject(s)
Antiparkinson Agents/pharmacology , Behavior, Animal/drug effects , MPTP Poisoning/drug therapy , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Olfactory Bulb/drug effects , Olfactory Perception/drug effects , Smell/drug effects , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Choline O-Acetyltransferase/metabolism , Cholinergic Neurons/drug effects , Cholinergic Neurons/metabolism , Cholinergic Neurons/pathology , Disease Models, Animal , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Locomotion/drug effects , MPTP Poisoning/chemically induced , MPTP Poisoning/metabolism , MPTP Poisoning/physiopathology , Male , Mice, Inbred C57BL , Olfactory Bulb/metabolism , Olfactory Bulb/pathology , Olfactory Bulb/physiopathology , Signal Transduction , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Many studies reveal that BAG3 plays a critical role in the regulation of protein degradation via macroautophagy. However, it remains unknown whether BAG3 affects the quality control of α-synuclein (SNCA), a Parkinson's disease-related protein. In this study, we demonstrated the increases of BAG3 expression in the ventral midbrain of SNCAA53T transgenic mice and also in MG132-treated PC12 cells overexpressing wild-type SNCA (SNCAWT-PC12). Moreover, we showed that BAG3 overexpression was sufficient to enhance the autophagy activity while knockdown of Bag3 reduced it in SNCAWT-PC12 cells. Immunoprecipitation revealed that BAG3 interacted with heat shock protein 70 and sequestosome 1. The immunostaining also showed the perinuclear accumulation and colocalization of BAG3 with these 2 proteins, as well as with LC3 dots in tyrosine hydroxylase-positive neurons in the midbrain of SNCAA53T mice. BAG3 overexpression was able to modulate SNCA degradation via macroautophagy which was prevented by Atg5 knockdown. Taken together, these results indicate that BAG3 plays a relevant role in regulating SNCA clearance via macroautophagy, and the heat shock protein 70-BAG3-sequestosome 1 complex may be involved in this process.
Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Apoptosis Regulatory Proteins/physiology , Autophagy/genetics , Autophagy/physiology , alpha-Synuclein/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Gene Expression , HSP70 Heat-Shock Proteins/physiology , Male , Mesencephalon/metabolism , Mice, Transgenic , PC12 Cells , Rats , Sequestosome-1 Protein/physiologyABSTRACT
Background Although pain is one of the most distressing non-motor symptoms among patients with Parkinson's disease, the underlying mechanisms of pain in Parkinson's disease remain elusive. The aim of the present study was to investigate the role of serotonin (5-hydroxytryptamine) in the rostral ventromedial medulla (RVM) and spinal cord in pain sensory abnormalities in a 6-hydroxydopamine-treated rat model of Parkinson's disease. Methods The rotarod test was used to evaluate motor function. The radiant heat test and von Frey test were conducted to evaluate thermal and mechanical pain thresholds, respectively. Immunofluorescence was used to examine 5-hydroxytryptamine neurons and fibers in the rostral ventromedial medulla and spinal cord. High-performance liquid chromatography was used to determine 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels. Results The duration of running time on the rotarod test was significantly reduced in 6-hydroxydopamine-treated rats. Nociceptive thresholds of both mechanical and heat pain were reduced compared to sham-treated rats. In addition to the degeneration of cell bodies and fibers in the substantia nigra pars compacta, the number of rostral ventromedial medulla 5-hydroxytryptamine neurons and 5-hydroxytryptamine fibers in the spinal dorsal horn was dramatically decreased. 5-Hydroxytryptamine concentrations in both the rostral ventromedial medulla and spinal cord were reduced. Furthermore, the administration of citalopram significantly attenuated pain hypersensitivity. Interestingly, Intra-rostral ventromedial medulla (intra-RVM) microinjection of 5,7-dihydroxytryptamine partially reversed pain hypersensitivity of 6-hydroxydopamine-treated rats. Conclusions These results suggest that the decreased 5-hydroxytryptamine contents in the rostral ventromedial medulla and spinal dorsal horn may be involved in hyperalgesia in the 6-hydroxydopamine-induced rat model of Parkinson's disease.
