Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the m...Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.展开更多
The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration.However,it remains largely unclear how PINK1 and Parkin a...The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration.However,it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains.This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals.Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin.Recently,we showed that the PINK1 kinase is selectively expressed as a truncated form(PINK1–55)in the primate brain.In the present study,we used multiple antibodies,including our recently developed monoclonal anti-PINK1,to validate the selective expression of PINK1 in the primate brain.We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages,which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains.PINK1 was enriched in the membrane-bound fractionations,whereas Parkin was soluble with a distinguishable distribution.Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes,though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress.These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.展开更多
The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopam...The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopaminergic neuron survival and physiology in cell culture experiments and animal models.This prompted the idea to try GDNF/RET signaling as a therapeutic approach to treat Parkinson’s disease with the hallmark of dopaminergic cell death in the substantia nigra of the midbrain.Despite several clinical trials with GDNF in Parkinson’s disease patients,which mainly focused on optimizing the GDNF delivery technique,benefits were only seen in a few patients.In general,the endpoints did not show significant improvements.This suggests that it will be helpful to learn more about the basic biology of this fascinating but complicated GDNF/RET signaling system in the dopaminergic midbrain and about recent developments in the field to facilitate its use in the clinic.Here we will refer to the latest publications and point out important open questions in the field.展开更多
We have performed a complete screening of the Parkin gene (PRKN2) and looked for p.Gly2019Ser (G2019S) and p.Arg1441Gly (R1441G) LRRK2/dardarin gene mutations in twenty seven patients with Parkinson’s disease (PD) wi...We have performed a complete screening of the Parkin gene (PRKN2) and looked for p.Gly2019Ser (G2019S) and p.Arg1441Gly (R1441G) LRRK2/dardarin gene mutations in twenty seven patients with Parkinson’s disease (PD) with an age at onset younger than 50 years (EOPD), living in Gipuzkoa (Basque Country, Spain). Thirteen of them (48%) were PRKN2 mutation carriers. The c.255-256DelA mutation was the most frequent, followed by a deletion involving exons 3 and 4. A deletion involving exons 3 and 12 of the PRKN2 gene and R1441G LRRK2 mutation was found together in one PD patient. Four out of fourteen PRKN2 negative patients carried the p.G2019S mutation. Both PRKN2 mutation carriers and non-carriers presented frequently with family history (10 PRKN2 mutation carriers and 8 PRKN2 non-carriers);in fact, five patients without a known gene mutation had a first degree relative affected, suggesting another monogenic disease. PRKN2 carriers presented with a younger age at onset (36.7 vs. 41.7) and more benign disease progression. Indeed, those PD patients younger than forty who initially presented with unilateral tremor became shortly bilateral. Relatively, symmetric parkinsonism and slow disease progression carried more frequently PRKN2 mutations than patients with unilateral akinetic rigid parkinsonism and age at onset later than 40 years. As expected in a recessive disease, PRKN2 patients present more often with affected siblings and unaffected patients. The G2019S LRRK2 mutation, less prevalent than R1441G in our area, may be also a frequent cause of PD in EOPD (4 patients).展开更多
Mitochondria are critical cellular energy resources and are central to the life of the neuron.Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial q...Mitochondria are critical cellular energy resources and are central to the life of the neuron.Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis.Mature neurons are postmitotic and consume substantial energy,thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria.Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases.However,more work is needed to study mitophagy pathway components as potential therapeutic targets.In this review,we briefly discuss the characteristics of nonselective autophagy and selective autophagy,including ERphagy,aggrephagy,and mitophagy.We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions.Next,we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy.Importantly,we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.Last,we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases.Together,our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.展开更多
Parkinson’s disease(PD)is the second most common neurodegenerative disease.Increasing evidence supports that dysregulation of autophagy and mitochondrial function are closely related with PD pathogenesis.In this revi...Parkinson’s disease(PD)is the second most common neurodegenerative disease.Increasing evidence supports that dysregulation of autophagy and mitochondrial function are closely related with PD pathogenesis.In this review,we briefly summarized autophagy pathway,which consists of macroautophagy,microautophagy and chaperone-mediated autophagy(CMA).Then,we discussed the involvement of mitochondrial dysfunction in PD pathogenesis.We specifically reviewed the recent developments in the relationship among several PD related genes,autophagy and mitochondrial dysfunction,followed by the therapeutic implications of these pathways.In conclusion,we propose that autophagy activity and mitochondrial homeostasis are of high importance in the pathogenesis of PD.Better understanding of these pathways can shed light on the novel therapeutic methods for PD prevention and amelioration.展开更多
The second most serious neurodegenerative disease is Parkinson’s disease(PD).Over the past several decades,a strong body of evidence suggests that PD can begin years before the hallmark clinical motor symptoms appear...The second most serious neurodegenerative disease is Parkinson’s disease(PD).Over the past several decades,a strong body of evidence suggests that PD can begin years before the hallmark clinical motor symptoms appear.Biomarkers for PD are urgently needed to differentiate between neurodegenerative disorders,screen novel therapeutics,and predict eventual clinical PD before the onset of symptoms.Some clinical evaluations and neuroimaging techniques have been developed in the last several years with some success in this area.Moreover,other strategies have been utilized to identify biochemical and genetic markers associated with PD leading to the examination of PD progression and pathogenesis in cerebrospinal fluid,blood,or saliva.Finally,interesting results are surfacing from preliminary studies using known PD-associated genetic mutations to assess potential premotor PD biomarkers.The current review highlights recent advances and underscores areas of potential advancement.展开更多
Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,characterized primarily by the loss of dopaminergic neurons in substantia nigra.The pathogenic mechanisms of PD remain unclear,and no effe...Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,characterized primarily by the loss of dopaminergic neurons in substantia nigra.The pathogenic mechanisms of PD remain unclear,and no effective therapy currently exists to stop neurodegeneration in this debilitating disease.The identification of mutations in mitochondrial serine/threonine kinase PINK1 or E3 ubiquitin-protein ligase parkin as the cause of autosomal recessive PD opens up new avenues for uncovering neuroprotective pathways and PD pathogenic mechanisms.Recent studies reveal that PINK1 translocates to the outer mitochondrial membrane in response to mitochondrial depolarization and phosphorylates ubiquitin at the residue Ser65.The phosphorylated ubiquitin serves as a signal for activating parkin and recruiting autophagy receptors to promote clearance of damaged mitochondria via mitophagy.Emerging evidence has begun to indicate a link between impaired ubiquitin phosphorylation-dependent mitophagy and PD pathogenesis and supports the potential of Ser65-phosphorylated ubiquitin as a biomarker for PD.The new mechanistic insights and phenotypic screens have identified multiple potential therapeutic targets for PD drug discovery.This review highlights recent advances in understanding ubiquitin phosphorylation in mitochondrial quality control and PD pathogenesis and discusses how these findings can be translated into novel approaches for PD diagnostic and therapeutic development.展开更多
The mutation of the Parkin gene is a cause of familial Parkinson’s disease.A growing body of evidence suggests that Parkin also functions as a tumor suppressor.Parkin is an ubiquitin E3 ligase,and plays important rol...The mutation of the Parkin gene is a cause of familial Parkinson’s disease.A growing body of evidence suggests that Parkin also functions as a tumor suppressor.Parkin is an ubiquitin E3 ligase,and plays important roles in a variety of cellular processes implicated in tumorigenesis,including cell cycle,cell proliferation,apoptosis,metastasis,mitophagy and metabolic reprogramming.Here we review the role and mechanism of Parkin in cancer.展开更多
While early-onset Parkinson’s disease(EOPD)caused by mutations in the parkin gene(PRKN)tends to have a relatively benign course compared to genetically undetermined(GU)-EOPD,the exact underlying mechanisms remain elu...While early-onset Parkinson’s disease(EOPD)caused by mutations in the parkin gene(PRKN)tends to have a relatively benign course compared to genetically undetermined(GU)-EOPD,the exact underlying mechanisms remain elusive.We aimed to search for the differences between PRKN-EOPD and GU-EOPD by dopamine transporter(DAT)and glucose metabolism positron-emission-tomography(PET)imaging.Twelve patients with PRKN-EOPD and 16 with GU-EOPD who accepted both ^(11)C-2b-carbomethoxy-3b-(4-trimethylstannylphenyl)tropane(^(11)C-CFT)and ^(18)F-fluorodeoxyglucose PET were enrolled.The ^(11)C-CFT uptake was analyzed on both regional and voxel levels,whereas glucose metabolism was assessed in a voxel-wise fashion.Correlations between DAT and glucose metabolism imaging,DAT imaging and clinical severity,as well as glucose metabolism imaging and clinical severity were explored.Both clinical symptoms and DAT-binding pat-terns in the posterior putamen were highly symmetrical in patients with PRKN-EOPD,and dopaminergic dysfunction in the ipsilateral putamen was severer in patients with PRKN-EOPD than GU-EOPD.Meanwhile,the DAT binding was associ-ated with the severity of motor dysfunction in patients with GU-EOPD only.Patients with PRKN-EOPD showed increased glucose metabolism in the contralateral medial frontal gyrus(supplementary motor area(SMA)),contralateral substantia nigra,contralateral thalamus,and contralateral cerebellum.Notably,glucose metabolic activity in the contralateral medial frontal gyrus was inversely associated with regional DAT binding in the bilateral putamen.Patients with PRKN-EOPD showed enhanced metabolic connectivity within the bilateral putamen,ipsilateral paracentral and precentral lobules,and the ipsilateral SMA.Collectively,compared to GU-EOPD,PRKN-EOPD is characterized by symmetrical,more severe dopaminergic dysfunction and relative increased glucose metabolism.Meanwhile,SMA with elevated glucose metabolism and enhanced connectivity may act as compensatory mechanisms in PRKN-EOPD.展开更多
Background:Mitochondrial dysfunction plays a prominent role in the pathogenesis of Parkinson’s disease(PD),and several genes linked to familial PD,including PINK1(encoding PTEN-induced putative kinase 1[PINK1])and PA...Background:Mitochondrial dysfunction plays a prominent role in the pathogenesis of Parkinson’s disease(PD),and several genes linked to familial PD,including PINK1(encoding PTEN-induced putative kinase 1[PINK1])and PARK2(encoding the E3 ubiquitin ligase Parkin),are directly involved in processes such as mitophagy that maintain mitochondrial health.The dominant p.D620N variant of vacuolar protein sorting 35 ortholog(VPS35)gene is also associated with familial PD but has not been functionally connected to PINK1 and PARK2.Methods:To better mimic and study the patient situation,we used CRISPR-Cas9 to generate heterozygous human SH-SY5Y cells carrying the PD-associated D620N variant of VPS35.These cells were treated with a protonophore carbonyl cyanide m-chlorophenylhydrazone(CCCP)to induce the PINK1/Parkin-mediated mitophagy,which was assessed using biochemical and microscopy approaches.Results:Mitochondria in the VPS35-D620N cells exhibited reduced mitochondrial membrane potential and appeared to already be damaged at steady state.As a result,the mitochondria of these cells were desensitized to the CCCPinduced collapse in mitochondrial potential,as they displayed altered fragmentation and were unable to accumulate PINK1 at their surface upon this insult.Consequently,Parkin recruitment to the cell surface was inhibited and initiation of the PINK1/Parkin-dependent mitophagy was impaired.Conclusion:Our findings extend the pool of evidence that the p.D620N mutation of VPS35 causes mitochondrial dysfunction and suggest a converging pathogenic mechanism among VPS35,PINK1 and Parkin in PD.展开更多
Epidemiological studies suggest a direct link between melanoma and Parkinson＇s disease（PD）; however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and P...Epidemiological studies suggest a direct link between melanoma and Parkinson＇s disease（PD）; however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28 K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson＇s disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases.展开更多
线粒体自噬(mitophagy)是指特异清除受损或多余线粒体的过程,是一种重要的线粒体质量控制机制。线粒体自噬功能障碍或线粒体自噬过度激活都会破坏线粒体稳态,影响机体健康甚至导致死亡。主要讨论了在酵母和哺乳动物细胞中发现的正向调...线粒体自噬(mitophagy)是指特异清除受损或多余线粒体的过程,是一种重要的线粒体质量控制机制。线粒体自噬功能障碍或线粒体自噬过度激活都会破坏线粒体稳态,影响机体健康甚至导致死亡。主要讨论了在酵母和哺乳动物细胞中发现的正向调控线粒体自噬的机制:在酵母中,线粒体自噬是由自噬相关蛋白32(autophagy-related protein 32,Atg32)介导的;而哺乳动物体内线粒体自噬的调控途径主要有3种:PTEN诱导激酶1(PTEN-induced kinase 1,PINK1)/E3泛素连接酶Parkin途径、类NIP3蛋白X(NIP3-like protein X,Nix)途径、携带FUN14结构域蛋白1(FUN14 domain-containing protein 1,UNDC1)途径,此外,还有几种新发现的线粒体自噬受体也能够介导线粒体的特异清除。并对目前研究较少的线粒体自噬的负调控机制进行了综述。最后探讨了线粒体自噬功能异常与人类疾病(如帕金森症)的关联。通过深入剖析线粒体自噬发生的分子机制,以期为进一步研究与线粒体自噬功能异常相关的疾病的治疗提供理论基础。展开更多
基金supported by the Key Science and Technology Research of Henan Province,No.222102310351(to JW)Luoyang 2022 Medical and Health Guiding Science and Technology Plan Project,No.2022057Y(to JY)Henan Medical Science and Technology Research Program Province-Ministry Co-sponsorship,No.SBGJ202002099(to JY)。
文摘Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.
基金supported by the National Natural Science Foundation of China,Nos.32070534(to WY),32370567(to WY),82371874(to XL),81830032(to XL),82071421(to SL)Key Field Research and Development Program of Guangdong Province,No.2018B030337001(to XL)+2 种基金Guangzhou Key Research Program on Brain Science,No.202007030008(to XL)Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(to XL)Guangdong Basic and Applied Basic Research Foundation,Nos.2022A1515012301(to WY),2023B1515020031(to WY).
文摘The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration.However,it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains.This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals.Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin.Recently,we showed that the PINK1 kinase is selectively expressed as a truncated form(PINK1–55)in the primate brain.In the present study,we used multiple antibodies,including our recently developed monoclonal anti-PINK1,to validate the selective expression of PINK1 in the primate brain.We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages,which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains.PINK1 was enriched in the membrane-bound fractionations,whereas Parkin was soluble with a distinguishable distribution.Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes,though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress.These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.
基金BRACE-Dementia Research,UK(ERK)Alzheimer’s Research UKthe Northcott Devon Medical Foundation(to JAC and ERK)for financial support。
文摘The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopaminergic neuron survival and physiology in cell culture experiments and animal models.This prompted the idea to try GDNF/RET signaling as a therapeutic approach to treat Parkinson’s disease with the hallmark of dopaminergic cell death in the substantia nigra of the midbrain.Despite several clinical trials with GDNF in Parkinson’s disease patients,which mainly focused on optimizing the GDNF delivery technique,benefits were only seen in a few patients.In general,the endpoints did not show significant improvements.This suggests that it will be helpful to learn more about the basic biology of this fascinating but complicated GDNF/RET signaling system in the dopaminergic midbrain and about recent developments in the field to facilitate its use in the clinic.Here we will refer to the latest publications and point out important open questions in the field.
文摘We have performed a complete screening of the Parkin gene (PRKN2) and looked for p.Gly2019Ser (G2019S) and p.Arg1441Gly (R1441G) LRRK2/dardarin gene mutations in twenty seven patients with Parkinson’s disease (PD) with an age at onset younger than 50 years (EOPD), living in Gipuzkoa (Basque Country, Spain). Thirteen of them (48%) were PRKN2 mutation carriers. The c.255-256DelA mutation was the most frequent, followed by a deletion involving exons 3 and 4. A deletion involving exons 3 and 12 of the PRKN2 gene and R1441G LRRK2 mutation was found together in one PD patient. Four out of fourteen PRKN2 negative patients carried the p.G2019S mutation. Both PRKN2 mutation carriers and non-carriers presented frequently with family history (10 PRKN2 mutation carriers and 8 PRKN2 non-carriers);in fact, five patients without a known gene mutation had a first degree relative affected, suggesting another monogenic disease. PRKN2 carriers presented with a younger age at onset (36.7 vs. 41.7) and more benign disease progression. Indeed, those PD patients younger than forty who initially presented with unilateral tremor became shortly bilateral. Relatively, symmetric parkinsonism and slow disease progression carried more frequently PRKN2 mutations than patients with unilateral akinetic rigid parkinsonism and age at onset later than 40 years. As expected in a recessive disease, PRKN2 patients present more often with affected siblings and unaffected patients. The G2019S LRRK2 mutation, less prevalent than R1441G in our area, may be also a frequent cause of PD in EOPD (4 patients).
基金supported by the National Natural Science Foundation of China,Nos.82001211(to KY),82101241(to SW),and 82125032(to FL).
文摘Mitochondria are critical cellular energy resources and are central to the life of the neuron.Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis.Mature neurons are postmitotic and consume substantial energy,thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria.Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases.However,more work is needed to study mitophagy pathway components as potential therapeutic targets.In this review,we briefly discuss the characteristics of nonselective autophagy and selective autophagy,including ERphagy,aggrephagy,and mitophagy.We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions.Next,we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy.Importantly,we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.Last,we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases.Together,our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.
基金The works were supported by National Natural Science Foundation of China(Grant No.31371400)(Q.Y)and(Grant No.31671060)(Q.Y).
文摘Parkinson’s disease(PD)is the second most common neurodegenerative disease.Increasing evidence supports that dysregulation of autophagy and mitochondrial function are closely related with PD pathogenesis.In this review,we briefly summarized autophagy pathway,which consists of macroautophagy,microautophagy and chaperone-mediated autophagy(CMA).Then,we discussed the involvement of mitochondrial dysfunction in PD pathogenesis.We specifically reviewed the recent developments in the relationship among several PD related genes,autophagy and mitochondrial dysfunction,followed by the therapeutic implications of these pathways.In conclusion,we propose that autophagy activity and mitochondrial homeostasis are of high importance in the pathogenesis of PD.Better understanding of these pathways can shed light on the novel therapeutic methods for PD prevention and amelioration.
基金This work was supported by NIH grants AG033398,ES004696-5897,ES007033-6364,ES016873,ES019277,NS057567,and NS062684-6221.
文摘The second most serious neurodegenerative disease is Parkinson’s disease(PD).Over the past several decades,a strong body of evidence suggests that PD can begin years before the hallmark clinical motor symptoms appear.Biomarkers for PD are urgently needed to differentiate between neurodegenerative disorders,screen novel therapeutics,and predict eventual clinical PD before the onset of symptoms.Some clinical evaluations and neuroimaging techniques have been developed in the last several years with some success in this area.Moreover,other strategies have been utilized to identify biochemical and genetic markers associated with PD leading to the examination of PD progression and pathogenesis in cerebrospinal fluid,blood,or saliva.Finally,interesting results are surfacing from preliminary studies using known PD-associated genetic mutations to assess potential premotor PD biomarkers.The current review highlights recent advances and underscores areas of potential advancement.
基金Work in the authors’laboratories is supported by grants from National Institutions of Health(NS093550,GM103613,and NS092343)a pilot grant award from NIH-funded Emory Udall Parkinson’s Disease Center(P50 NS071669).
文摘Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,characterized primarily by the loss of dopaminergic neurons in substantia nigra.The pathogenic mechanisms of PD remain unclear,and no effective therapy currently exists to stop neurodegeneration in this debilitating disease.The identification of mutations in mitochondrial serine/threonine kinase PINK1 or E3 ubiquitin-protein ligase parkin as the cause of autosomal recessive PD opens up new avenues for uncovering neuroprotective pathways and PD pathogenic mechanisms.Recent studies reveal that PINK1 translocates to the outer mitochondrial membrane in response to mitochondrial depolarization and phosphorylates ubiquitin at the residue Ser65.The phosphorylated ubiquitin serves as a signal for activating parkin and recruiting autophagy receptors to promote clearance of damaged mitochondria via mitophagy.Emerging evidence has begun to indicate a link between impaired ubiquitin phosphorylation-dependent mitophagy and PD pathogenesis and supports the potential of Ser65-phosphorylated ubiquitin as a biomarker for PD.The new mechanistic insights and phenotypic screens have identified multiple potential therapeutic targets for PD drug discovery.This review highlights recent advances in understanding ubiquitin phosphorylation in mitochondrial quality control and PD pathogenesis and discusses how these findings can be translated into novel approaches for PD diagnostic and therapeutic development.
基金supported by grants to Z.F.from the NIH(R01CA227912)Rutgers Cancer Institute of New Jersey Pilot Award,and by grants to W.H.from the NIH(R01CA160558,R01CA203965)Ellison Medical Foundation.
文摘The mutation of the Parkin gene is a cause of familial Parkinson’s disease.A growing body of evidence suggests that Parkin also functions as a tumor suppressor.Parkin is an ubiquitin E3 ligase,and plays important roles in a variety of cellular processes implicated in tumorigenesis,including cell cycle,cell proliferation,apoptosis,metastasis,mitophagy and metabolic reprogramming.Here we review the role and mechanism of Parkin in cancer.
基金the grants from Ministry of Science and Technology of China(No.2016YFC1306504)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)+7 种基金ZJLab,and National Nature Science Foundation of China(Nos.91949118,81771372)Chuan-Tao Zuo received the research funding from the National Natural Science Foundation of China(Nos.82021002,81971641,81671239,and 81361120393)Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01)Science and Technology Commission of Shanghai Municipality(Nos.19441903500 and 17JC1401600)Shanghai Aging and Maternal and Child Health Research Special Project(No.2020YJZX0111)Clinical Research Plan of Shanghai Hospital Development Center(No.SHDC2020CR1038B)Science and Technology Innovation 2030 Major Project(No.2022ZD0211600)Feng-Tao Liu received the grant of the National Nature Science Foundation of China(Nos.82171252,81701250).
文摘While early-onset Parkinson’s disease(EOPD)caused by mutations in the parkin gene(PRKN)tends to have a relatively benign course compared to genetically undetermined(GU)-EOPD,the exact underlying mechanisms remain elusive.We aimed to search for the differences between PRKN-EOPD and GU-EOPD by dopamine transporter(DAT)and glucose metabolism positron-emission-tomography(PET)imaging.Twelve patients with PRKN-EOPD and 16 with GU-EOPD who accepted both ^(11)C-2b-carbomethoxy-3b-(4-trimethylstannylphenyl)tropane(^(11)C-CFT)and ^(18)F-fluorodeoxyglucose PET were enrolled.The ^(11)C-CFT uptake was analyzed on both regional and voxel levels,whereas glucose metabolism was assessed in a voxel-wise fashion.Correlations between DAT and glucose metabolism imaging,DAT imaging and clinical severity,as well as glucose metabolism imaging and clinical severity were explored.Both clinical symptoms and DAT-binding pat-terns in the posterior putamen were highly symmetrical in patients with PRKN-EOPD,and dopaminergic dysfunction in the ipsilateral putamen was severer in patients with PRKN-EOPD than GU-EOPD.Meanwhile,the DAT binding was associ-ated with the severity of motor dysfunction in patients with GU-EOPD only.Patients with PRKN-EOPD showed increased glucose metabolism in the contralateral medial frontal gyrus(supplementary motor area(SMA)),contralateral substantia nigra,contralateral thalamus,and contralateral cerebellum.Notably,glucose metabolic activity in the contralateral medial frontal gyrus was inversely associated with regional DAT binding in the bilateral putamen.Patients with PRKN-EOPD showed enhanced metabolic connectivity within the bilateral putamen,ipsilateral paracentral and precentral lobules,and the ipsilateral SMA.Collectively,compared to GU-EOPD,PRKN-EOPD is characterized by symmetrical,more severe dopaminergic dysfunction and relative increased glucose metabolism.Meanwhile,SMA with elevated glucose metabolism and enhanced connectivity may act as compensatory mechanisms in PRKN-EOPD.
基金D.S.V.is supported by a Rosalind Franklin Fellowship from the University of Groningen(UG).K.Y.M.is supported by the Jan Kornelis de Cock-Stichting and the U4 PhD program of the Behavioral and Cognitive Neuroscience Graduate School of the UG.M.M.is supported by an ALW Open Programme(ALWOP.355)F.R.is supported by ZonMW TOP(91217002)+5 种基金ALW Open Programme(ALWOP.310)Open Competition ENW-KLEIN(OCENW.KLEIN.118)Marie Sklodowska-Curie Cofund(713660)Marie Skłodowska Curie ETN(765912)grantsPart of this work was performed at the University Medical Centre Groningen Microscopy and Imaging Centre,which is sponsored by the Netherlands Organization for Scientific Research(NWO grants 40-00506-98-9021 and 175-010-2009-023)None of the funding bodies were involved in the collection,analysis and interpretation of data,nor in the writing of the manuscript.
文摘Background:Mitochondrial dysfunction plays a prominent role in the pathogenesis of Parkinson’s disease(PD),and several genes linked to familial PD,including PINK1(encoding PTEN-induced putative kinase 1[PINK1])and PARK2(encoding the E3 ubiquitin ligase Parkin),are directly involved in processes such as mitophagy that maintain mitochondrial health.The dominant p.D620N variant of vacuolar protein sorting 35 ortholog(VPS35)gene is also associated with familial PD but has not been functionally connected to PINK1 and PARK2.Methods:To better mimic and study the patient situation,we used CRISPR-Cas9 to generate heterozygous human SH-SY5Y cells carrying the PD-associated D620N variant of VPS35.These cells were treated with a protonophore carbonyl cyanide m-chlorophenylhydrazone(CCCP)to induce the PINK1/Parkin-mediated mitophagy,which was assessed using biochemical and microscopy approaches.Results:Mitochondria in the VPS35-D620N cells exhibited reduced mitochondrial membrane potential and appeared to already be damaged at steady state.As a result,the mitochondria of these cells were desensitized to the CCCPinduced collapse in mitochondrial potential,as they displayed altered fragmentation and were unable to accumulate PINK1 at their surface upon this insult.Consequently,Parkin recruitment to the cell surface was inhibited and initiation of the PINK1/Parkin-dependent mitophagy was impaired.Conclusion:Our findings extend the pool of evidence that the p.D620N mutation of VPS35 causes mitochondrial dysfunction and suggest a converging pathogenic mechanism among VPS35,PINK1 and Parkin in PD.
基金support from I-CORE (grant number 41/11)the Israel Cancer Association (ICA) (grant number 20150101)+2 种基金Israel Cancer Research Fund (ICRF) (grant number RCBA-11706)Fritz Thyssen Stiftung (grant number AZ.10.12.1.188)Marie Curie Career Integration Grants (CIG) (grant number 293594)
文摘Epidemiological studies suggest a direct link between melanoma and Parkinson＇s disease（PD）; however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28 K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson＇s disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases.
文摘线粒体自噬(mitophagy)是指特异清除受损或多余线粒体的过程,是一种重要的线粒体质量控制机制。线粒体自噬功能障碍或线粒体自噬过度激活都会破坏线粒体稳态,影响机体健康甚至导致死亡。主要讨论了在酵母和哺乳动物细胞中发现的正向调控线粒体自噬的机制:在酵母中,线粒体自噬是由自噬相关蛋白32(autophagy-related protein 32,Atg32)介导的;而哺乳动物体内线粒体自噬的调控途径主要有3种:PTEN诱导激酶1(PTEN-induced kinase 1,PINK1)/E3泛素连接酶Parkin途径、类NIP3蛋白X(NIP3-like protein X,Nix)途径、携带FUN14结构域蛋白1(FUN14 domain-containing protein 1,UNDC1)途径,此外,还有几种新发现的线粒体自噬受体也能够介导线粒体的特异清除。并对目前研究较少的线粒体自噬的负调控机制进行了综述。最后探讨了线粒体自噬功能异常与人类疾病(如帕金森症)的关联。通过深入剖析线粒体自噬发生的分子机制,以期为进一步研究与线粒体自噬功能异常相关的疾病的治疗提供理论基础。
