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Mitophagy in neurodegenerative disease pathogenesis

Neural Regeneration Research 2024年第5期19卷 998-1005页

作者： Kan Yang yuqing Yan Anni yu Ru zhang yuefang zhang Zilong {2..Zhengyi Li Qianlong zhang Shihao Wu Fei Li Department of Developmental and Behavioural Pediatric&Child Primary Care Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children’s Environmental HealthXinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Center for Excellence in brain science and Intelligence Technology Institute of NeuroscienceState Key Laboratory of NeuroscienceCAS Key Laboratory of Primate NeurobiologyChinese Academy of SciencesShanghaiChina College of Materials and Chemical Engineering Hunan Institute of EngineeringXiangtanHunan ProvinceChina School of Medicine Yunnan UniversityKunmingYunnan ProvinceChina Songjiang Research institute Shanghai Jiao Tong University School of MedicineShanghaiChina Neurosurgery Department Kunming Yenan HospitalKunmingYunnan ProvinceChina

Mitochondria are critical cellular energy resources and are central to the life of the *** selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and *** neurons are postmitotic and consume substantial energy,thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional *** evidence indicates that mitophagy is pivotal to the pathogenesis of neurological ***,more work is needed to study mitophagy pathway components as potential therapeutic *** this review,we briefly discuss the characteristics of nonselective autophagy and selective autophagy,including ERphagy,aggrephagy,and *** then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological ***,we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate ***,we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral ***,we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative ***,our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

关键词： Alzheimer’s disease amyotrophic lateral sclerosis autophagy mitochondria mitophagy mitophagy receptor Parkin Parkinson’s disease PINK1

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Involvement of the anterior cingulate cortex in the affective pain

Involvement of the anterior cingulate cortex in the affectiv...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： yu-qiu zhang institute of neurobiology,institutes of brain science and state key laboratory of medical neurobiology,{2..hanghai 2..032..hina.

Pain is a multidimensional conscious experience including sensory and affective *** former has been extensively studied,while the latter is poorly *** evidence from morphological, electrophysiological,neuroimaging,and behavioral studies as well as clinical observations indicate that the anterior cingulate cortex(ACC) is a key structure that contributes to pain negative affect or *** formalin-induced conditioned place avoidance(F-CPA) in rats,which is believed to reflect the pain-related negative emotion,we found that lesions of the bilateral ACC markedly blocked the painful stimulation-induced CPA,but not non-painful fear stimulation-induced CPA(Gao et al.,2..4).Intracerebroventricular or intra-rostral ACC(rACC) administration of NMDA receptor antagonist DL-2..mino-5-phosphonovaleric acid(APV),but not AMPA/KA receptor antagonist 6,7- dinitroquinoxaline-2..-dione(DNQX),significantly decreased both conditioning scores of F-CPA(Lei et al.,2..4).Similarly, intra-rACC injection of 7-Chlorokynurenate(7C1-KYNA),an antagonist of the glycine site of NMDA receptors,can also effectively eliminate the induction of ***,degradation of endogenous D-serine,an endogenous ligand for the glycine site of NMDA receptors,by DAAO(D-amino acid oxidase),an endogenous D-serine degrading enzyme, effectively inhibited NMDA-evoked currents and attenuated F-CPA scores,but did not affect formalin-induced acute nociceptive behaviors,suggesting that endogenous D-serine in the rACC is necessary for NMDA receptor-mediated pain-related aversion(Ren et al.,2..6).Extracellular signal-regulated kinase(ERK),a family member of mitogen-activated protein kinases(MAPKs),has been implicated in NMDA-dependent synaptic *** of NMD A receptor markedly increased expression levels of phosphor-ERK(pERK) through a Ca-dependent mechanism,and PKA might mediate the NMDA-dependent ERK *** ERK translocates from the cytosol to the

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Involvement of estrogen in pain modulation in ovariectomized adult rats

Involvement of estrogen in pain modulation in ovariectomized...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Li-Hong LI,Zhi-Qi ZHAO,yu-qiu zhang~* {2..of {2..institutes of brain science and state key laboratory of medical neurobiology,fudan university,Shanghai 2..032..hina

＜正＞Objective Many pain syndromes are prevalent in women and it is known that estrogen plays a key role in pain *** study was to measure the basal nociceptive responses to mechanical and thermal stimuli in native,sham and ovariectomized（OVX） adult SD rats and to study if estrogen could modulate *** We used von Frey test （hindlimbs）,Hargreaves’ test（hindlimbs） and tail flick test（proximal and distal tail） in different groups from pre-surgery till seven weeks after surgery one or two times per *** body weight,uterus weight and vaginal smear were monitored to ensure the success of the *** We found that rats developed allodynia in von Frey test and hyperalgesia in tail flick test from 4-5 weeks after OVX till 7 weeks after surgery but not in Hargreaves’ *** body weight increased and uterus weight decreased significantly in OVX group than in the other *** all of these phenomena could be reversed by the replacement of 17 *** The estrogen plays an important role in stabilizing the basal pain threshold of female rats.

关键词： pain OVX estrogen allodynia hyperalgesia

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Effect of OVX on nociceptive responses and possible mechanisms in adult female rats

Effect of OVX on nociceptive responses and possible mechanis...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Li-Hong LI,Zhi-Qi ZHAO,yu-qiu zhang~* {2..of {2..institutes of brain science and state key laboratory of medical neurobiology,fudan university,Shanghai 2..032..hina

＜正＞Objective Estrogen plays a key role in pain *** the effect is inconsistent and the mechanism is still *** study used OVX rat model to measure the pain behavior in basal,inflammatory and neuropathic pain（CCI model）and to study the possible *** We used the behavioral test:von Frey test （hindlimbs）,Hargreaves’test（hindlimbs）,tail flick test（proximal and distal tail）and formalin test in different groups to measure the nociceptive *** location of estrogen receptors（ERs）were identified by immunofluorescence *** Western blot was used to measure the protein level of ER and ***（1）Significant allodynia and hyperalgesia appeared 5 weeks post-OVX surgery and could be attenuated by long term 17β-estradiol（E2..replacement（s.c,1 week）.But CCI did not produce further decrease of mechanical pain threshold in OVX rats. This indicated the relatively lower level of estrogen might inhibit the allodynia accompanied by neuropathic pain. （2..ouble immunofluorescence showed co-localization of ERa and ERβwith NeuN（neuronal marker）but not with GFAP（astrocyte marker）and OX42..icroglia marker）in spinal.（3）ERαand Akt were up-regulated in 5 weeks after OVX surgery and could be restored after E2..dministration.（4）The formalin nociceptor responses were decreased after intrathecal injection of PI3K inhibitor（wortmannin）.Conclusion ERain spinal neuron may play an important role in the induction of hyperalgesia and allodynia in OVX rats through PI3K/Akt.

关键词： pain OVX estrogen allodynia hyperalgesia ERα ERβ CCI spinal neuron PI3K/Akt wortmannin

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Rapid effect of estrogen on glutamate related synaptic transmission and plasticity in the anterior cingulate cortex

Rapid effect of estrogen on glutamate related synaptic trans...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Xiao XIAO,Yan zhang,Zhi-Qi ZHAO,yu-qiu zhang~* {2..of neurobiology,institutes of brain science and state key laboratory of medical neurobiology,fudan university,Shanghai 2..032..hina

＜正＞Classically,estrogen has multiple actions in the brain via genomic mechanisms which generally take several *** present study was designed to examine that whether estrogen regulates glutamatergic transmission and plasticity within minutes and what is the possible mechanisms underlying the estrogen-induced rapid effects in the anterior cingulate cortex（ACC）.Immunohistochemistry results revealed that estrogen receptors（ERs） were highly expressed in glutamatergic neurons of the ***-cell recording from ACC slices results showed that estrogen enhanced the glutamatergic excitatory postsynaptic currents（EPSCs） in a dose-dependent ***,the affect of estrogen on AMPA and NMDA transmission exhibited an opposite manifestation:NMDA-mediated EPSCs（NMDAEPSCs） were significantly enhanced;whereas AMPA-EPSCs were remarkably *** fast onset effect of enhanced NMDA-EPSCs,within 6 minutes bath application of estrogen,lasted for more than 30 minutes（NMDA- LTP）.This NMDA-LTP was blocked by ER antagonist（ICI 182..0） and was mimicked by E-BSA,a specific agonist of membrane ***,the induction of estrogen-induced NMDA-LTP was also prevented by NR2..inhibitor and PKA *** together,these findings implicate that estrogen has rapid effects on glutamate transmission in ACC ***,estrogen-induced chemical NMDA-LTP is at least partially mediated by membrane ***2..KA pathway may play a critical role in estrogen-induced NMDA-LTP.

关键词： estrogen rapid effect NMDA receptor LTP anterior cingulate cortex

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Acute effects of 17β -estradiol on excitatory synaptic transmission and long-term potentiation in rat spinal dorsal horn

Acute effects of 17β -estradiol on excitatory synaptic tran...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yan zhang,Xiao XIAO,Zhi-Qi ZHAO,yu-qiu zhang~* {2..of neurobiology,institutes of brain science and state key laboratory of medical neurobiology,fudan university,Shanghai 2..032..hina

＜正＞Discussions about how estrogen modulates pain sensitivity have largely focused on genomic actions via nuclear receptors,but its rapid effects on synaptic transmission in nociceptive pathways have not been elucidated. The present study investigated the role of 17β-estradiol（E2..in the regulation of excitatory postsynaptic currents （EPSCs） and long-term potentiation（LTP） in the superficial dorsal horn（SDH,laminaeⅠ/Ⅱ） using spinal cord slices with attached dorsal root from juvenile（2.. weeks） *** and LTP of C-fiber evoked field potentials（fEPSPs） were recorded from SDH by stimulating dorsal root（DR） and Lissauer’s tract（LT） *** found that N-methyl-D-aspartate（NMDA）-induced currents were rapidly and dose-dependently enhanced by bath application of E2..hile a-amino-3-hydroxy-5-methyl-4-isoxazolepropri-anate（AMPA）-evoked currents were ***, short infusion of E2..ould induce chemical LTP of NMDA receptor-mediated EPSCs（NMDA-EPSCs） and longterm depression（LTD） of *** field potential recordings,slices perfused with E2..xhibited a significant enhancement of LTP magnitude compared with control slices which could be mimicked by E2..SA,an agonist of membrane estrogen receptor（mER）.The elevation effect of E2..n LTP ceiling could be prevented by ER antagonist ICI 182..** data suggest that estrogen modulates nociception probably by enhancing NMDA receptor-mediated currents or intensifying LTP via mER.

关键词： NMDA receptor LTP AMPA receptor estradiol spinal cord

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Identification and Characterization of a Rat Novel Gene RSEP4 Expressed Specifically in Central Nervous System

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Acta Biochimica et Biophysica Sinica 2004年第7期36卷 501-507页

作者： Xi-Dao WANG1,2..Ling-Wei KONG1, Zhi-Qin XIE1, yu-qiu zhang3, Zhi-Xin LIN2..Zhi-Qi ZHAO3,Lei yu4, and Nai-He JING1* 1 {2..of Molecular Cell Biology, {2..of Stem Cell Biology, institute of Biochemistry and Cell Biology, Shanghai institutes for Biological sciences, Chinese Academy of sciences, Graduate School of the Chinese Academy of sciences, Shanghai 2..031, China School of Life science and Biotechnology, 2.. Shanghai Jiaotong university, Shanghai 2..030, China institute of {12.. fudan university, Shanghai 2..433, China 3 4 Department of Cell Biology, {12..and Anatomy, College of Medicine, university of Cincinnati, Cincinnati, Ohio, USA laboratory of Molecular Cell Biology and Stem Cell Biology Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Graduate School of the Chinese Academy of Sciences Shanghai China

The low-abundantly expressed genes composed the majorities of the mRNAs expressed in the central nervous system (CNS), and were thought to be important for the normal brain functions. Through differential screening a low-abundance cDNA sublibrary with mRNA from neuropathic pain of chronic constriction injury (CCI) model, we have identified a novel rat gene, rat spinal-cord expression protein 4 gene (RSEP4). The total length of RSEP4 cDNA is 2..6 bp, with a 501 nucleotide open reading frame (ORF) that encodes a 167 amino acid polypeptide. Northern blot revealed that RSEP4 was expressed specifically in the CNS. In situ hybridization showed that the mRNA of RSEP4 was strongly expressed in the CA1, CA2..CA3 and DG regions of hippocampus, the Purkinje cells of cerebellum, and the small sensory neurons of dorsal horn and large motor neurons of ventral horn of spinal cord. Over-expression of RSEP4-EGFP fusion protein in the human embryonic kidney 2..T cells showed that RSEP4 protein was mainly localized in the cell cytoplasm. These results suggest that RSEP4 may play some roles in the CNS.

关键词： central nervous system (CNS) rat Northern blot in situ hybridization

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Changes in A-type voltage-gated K+ currents and capsaicin-activated currents on the small sensory neurons of dorsal root ganglion following the development of rat bone cancer pain

Changes in A-type voltage-gated K+ currents and capsaicin-ac...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Kai-Zheng DUAN,Qian XU,Zhi-Qi ZHAO,yu-qiu zhang~* {2..of {2..institutes of brain science,and state key laboratory of medical {2..{12..Shanghai,2..032..hina

Objective Although bone cancer pain is one of the most severe and common chronic pain conditions,the basic neurobiology of bone cancer pain is poorly *** Rat model of bone cancer pain was built by an injection of Walker2.. mammary gland carcinoma cells into the tibia medullary *** cell patch-clamp recording was carried out to investigate the functional changes of A-type voltage-gated K(Kv) channels and TRPV1 channel,which may play a fundamental role in determining the neural excitability,on acutely dissociated small neurons of dorsal root ganglion (DRG) from native or bone cancer pain *** A-type Kv currents were mainly expressed on the IB4-positive neurons,and the current densities were changed *** activating kinetics of the rapid inactivating A-type Kv channels was right shifted following bone cancer *** addition,as a natural character of TRPV1 channel,capsaicinactivated currents exhibits a tendency to be ***,at 2..days after inoculation carcinoma cells,the capsaicin-induced currents were less desensitized with 0.5μM capsaicin repeated treatment compared with native group, indicating that TRPV1 channel was sensitized in later phase of rat bone cancer *** findings may help us understanding the mechanisms underlying bone cancer pain,providing a potential strategy for therapies and improving the quality of life of cancer patients.

关键词： bone cancer pain A-type Kv channels TRPV1 small DRG neurons

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A-type potassium channel mechanism-based diclofenac therapy for bone cancer pain

A-type potassium channel mechanism-based diclofenac therapy ...

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中国生理学会第2..全国会员代表大会暨生理学学术大会

作者： Kai-Zheng DUAN,Qian XU,Zhi-Qi ZHAO,yu-qiu zhang~* {2..of {2..institutes of brain science and state key laboratory of medical neurobiology,fudan university, Shanghai 2..032..hina

Bone cancer pain significantly affects quality of life and survival of patients with *** mechanism-based therapies to treat this unique cancer-related pain is becoming *** we reported that A-type shaker family potassium channels involved the peripheral neuropathy of bone cancer pain in rats,and the possible mechanism of diclofenac,a non-steroidal anti-inflammatory agent(NSAID),therapy for this distinct chronic ***-cell recording results showed that there was a functional change of A-type potassium channels on small dorsal root ganglia(DRG) neurons during bone caner ***+ neurons mainly expressed the typical A-type potassium currents,which were increased at cancer 14 day,and then declined at cancer 2..*** and western blot analysis revealed mat bone cancer caused a profound reduction in Kv1.4 subunit at cancer 2..day,especially the Kv1.4 that is associated with A-type potassium currents in small DRG *** reduction in Kv1.4 was prevented by consecutively administrating with ***,diclofenac not only attenuated tumor burden,but also had a good analgesic effect for bone cancer pain by enhancing A-type potassium currents *** results extend the basic understanding on cancer pain and provide a new mechanism-based therapy for bone cancer pain.

关键词： bone cancer pain A-type Kv channels diclofenac small DRG neurons

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The plasticity of the dorsal root ganglion neurons following tetanic stimulation of sciatic nerve

The plasticity of the dorsal root ganglion neurons following...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Ling-Li LIANG Jia-Le YANG Ning LU yu-qiu zhang Zhi-Qi ZHAO~* {2..of {2..institutes of brain science and state key laboratory of medical neurobiology fudan university Shanghai 2..032..hina

＜正＞Objective Tetanic stimulation of the sciatic nerve elicits LTP of both A- and C-fiber-evoked field potentials in the spinal cord and long-lasting behavioral mechanical ***,the mechanism underlying these processes is poorly *** present study was to investigate the roles of the different types of dorsal root ganglion（DRG） sensory neurons in pain hypersensitivity induced by tetanic stimulation of the sciatic *** The adult male Sprague-Dawley rats were divided into two groups:tetanically stimulated group and sham-operated *** stimulation parameter was consisted of 10 trains of 2.. duration with 10 s intervals,100 Hz 0.5 ms rectangular pulses at 40 *** paw withdrawal threshold（PWT） to von-Frey hairs and the paw withdrawal latercy（PWL） to thermal stimuli were measured on days 1,4,7 and 14 after *** expression of neurofilament 2..（NF2..,a marker for myelinated A-fibers）, calcitonin gene-related peptide（CGRP,a marker for peptidergic primary afferents）,griffonia simplicifolia I isolectin B4（IB4, a marker of unmyelinated primary afferent neurons）,and activating transcription factor 3（ATF3,a neuronal marker of nerve injury） were observed in the L4 DRG using *** Sham operation failed to change in the mean PWTs and *** bilateral PWTs were decreased significantly following tetanic stimulation compared with the sham group（P＜0.001）.Likewise,tetanic stimulation of the sciatic nerve obviously shortened PWL to thermal stimulation in ipsilateral hindpaw compared with sham group（P＜0.001）.Immunofluorescence showed that the percent of NF2..-IR neurons in the ipsilateral L4 DRG did not change after tetanic stimulation of sciatic *** percent of IB4-IR neurons in the L4 DRG decreased significantly on day 4,7 and 14 after tetania（P＜0.001）.The percent of CGRP-IR neurons in L4 DRG decreased greatly on day 7 and 14 after tetania（P＜0.001）.Co-localization of ATF3 with NF2..,IB4 and CGRP showed that ATF3 express

关键词： dorsal root ganglion sensory neuron tetanic stimulation of sciatic nerve pain activating transcription factor 3(ATF3) neurofilament 2..(NF2..) calcitonin gene-related peptide(CGRP) griffonia simplicifolia isolectin B4(IB4)

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