Background:Parkinson’s disease(PD)is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies(LB).During the course of disease,misfoldedα-synu...Background:Parkinson’s disease(PD)is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies(LB).During the course of disease,misfoldedα-synuclein,the major constituent of LB,spreads to different regions of the brain in a prion-like fashion,giving rise to successive non-motor and motor symptoms.Etiology is likely multifactorial,and involves interplay among aging,genetic susceptibility and environmental factors.Main body:The prevalence of PD rises exponentially with age,and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death.However,the majority of those over the age of 80 do not have PD,thus other factors in addition to aging are needed to cause disease.Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk.Nevertheless,the causality of most environmental factors is not conclusively established,and alternative explanations such as reverse causality and recall bias cannot be excluded.The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD.Rare mutations as well as common variants in genes such as SNCA,LRRK2 and GBA are associated with risk of PD,but Mendelian causes collectively only account for 5%of PD and common polymorphisms are associated with small increase in PD risk.Heritability of PD has been estimated to be around 30%.Thus,aging,genetics and environmental factors each alone is rarely sufficient to cause PD for most patients.Conclusion:PD is a multifactorial disorder involving interplay of aging,genetics and environmental factors.This has implications on the development of appropriate animal models of PD which take all these factors into account.Common converging pathways likely include mitochondrial dysfunction,impaired autophagy,oxidative stress and neuroinflammation,which are associated with the accumulation and spread of misfoldedα-synuclein and neurodegeneration.Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.展开更多
This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson’s disease(PD).Mitochondria provide cellular energy in the...This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson’s disease(PD).Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation,but as an integral part of this process,superoxides and other reactive oxygen species are also produced.Excessive free radical production contributes to oxidative stress.Cells have evolved to handle such stress via various endogenous anti-oxidant proteins.One such family of proteins is the mitochondrial uncoupling proteins(UCPs),which are anion carriers located in the mitochondrial inner membrane.There are five known homologues(UCP1 to 5),of which UCP4 and 5 are predominantly expressed in neural cells.In a series of previous publications,we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium(MPP+;toxic metabolite of MPTP)and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential,and reducing oxidative stress.We also showed how their expression can be influenced by nuclear factor kappa-B(NF-B)signaling pathway specifically in UCP4.Furthermore,we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin(hormone produced by adipocytes)acting via UCP2 against MPP+-induced toxicity.There is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with PD.Their expression,which can be induced,may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease.展开更多
The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms.It does not take into account the disease etiology or the highly variable cli...The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms.It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder.The advent of next generation sequencing(NGS)has allowed for a system-wide,unbiased approach to identify all gene variants in the genome simultaneously.With the plethora of new genes being identified,genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia(SCA),hereditary spastic paraplegia(HSP)and Charcot-Marie-Tooth disease(CMT)has become widely accepted.It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease(PD)and amyotrophic lateral sclerosis(ALS).The observation of pleiotropy has emerged,with mutations in the same gene giving rise to diverse phenotypes,which further increases the complexity of phenotype-genotype correlation.Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene,presence of modifier genes,and oligogenic inheritance.Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms,translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies,and ultimately finding disease-modifying therapies for neurodegenerative disorders.展开更多
Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because ...Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because of the large number of voxels in the brain,multiple comparison correction(MCC)must be performed to reduce false positive rates,and a smaller P value(usually including either liberal or stringent MCC)is widely recommended[1].展开更多
There is a substantial amount of evidence from experimental parkinsonian models to show the neuroprotective effects of monoamine oxidase-B(MAOB)inhibitors.They have been studied for their potential disease-modifying e...There is a substantial amount of evidence from experimental parkinsonian models to show the neuroprotective effects of monoamine oxidase-B(MAOB)inhibitors.They have been studied for their potential disease-modifying effects in Parkinson’s disease(PD)for over 20 years in various clinical trials.This review provides a summary of the clinical trials and discusses the implications of their results in the context of disease-modification in PD.Earlier clinical trials on selegiline were confounded by symptomatic effects of this drug.Later clinical trials on rasagiline using delayed-start design provide newer insights in disease-modification in PD but success in achieving the aims of this strategy remain elusive due to obstacles,some of which may be insurmountable.展开更多
Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP),...Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.展开更多
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarit...Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarities between LRRK2-associated PD (LRRK2-PD) and sporadic PD, suggesting that LRRK2 is a potential disease modulator and a thera-peutic target in PD. LRRK2 mutant knock-in (KI) mouse models display subtle alterations in pathological aspects that mirror early-stage PD, including increased susceptibility of nigrostriatal neurotransmission, development of motor and non-motor symptoms, mitochondrial and autophagy-lysosomal defects and synucleinopathies. This review provides a rationale for the use of LRRK2 KI mice to investigate the LRRK2-mediated pathogenesis of PD and implications from current findings from different LRRK2 KI mouse models, and ultimately discusses the therapeutic potentials against LRRK2-associated pathologies in PD.展开更多
基金Tai Hung Fai Charitable Foundation-Edwin S H Leong Research Programmefor Parkinson's DiseaseThe Henry G.Leong Endowed Professorship in Neurology+1 种基金The Donation Fund for Neurology ResearchHealth and MedicalResearch Fund(HMRF),Food and Health Bureau,Hong Kong SA.R.
文摘Background:Parkinson’s disease(PD)is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies(LB).During the course of disease,misfoldedα-synuclein,the major constituent of LB,spreads to different regions of the brain in a prion-like fashion,giving rise to successive non-motor and motor symptoms.Etiology is likely multifactorial,and involves interplay among aging,genetic susceptibility and environmental factors.Main body:The prevalence of PD rises exponentially with age,and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death.However,the majority of those over the age of 80 do not have PD,thus other factors in addition to aging are needed to cause disease.Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk.Nevertheless,the causality of most environmental factors is not conclusively established,and alternative explanations such as reverse causality and recall bias cannot be excluded.The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD.Rare mutations as well as common variants in genes such as SNCA,LRRK2 and GBA are associated with risk of PD,but Mendelian causes collectively only account for 5%of PD and common polymorphisms are associated with small increase in PD risk.Heritability of PD has been estimated to be around 30%.Thus,aging,genetics and environmental factors each alone is rarely sufficient to cause PD for most patients.Conclusion:PD is a multifactorial disorder involving interplay of aging,genetics and environmental factors.This has implications on the development of appropriate animal models of PD which take all these factors into account.Common converging pathways likely include mitochondrial dysfunction,impaired autophagy,oxidative stress and neuroinflammation,which are associated with the accumulation and spread of misfoldedα-synuclein and neurodegeneration.Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.
基金This project is financially supported by the Henry G Leong Professorship in Neurology(SLH),the Donation Fund for Neurology Research(SLH),and Seed Funding for Basic Research,University of Hong Kong(PWLH)PWL Ho is supported by a Research Assistant ProfessorshipJWM Ho and HF Liu are supported by Postdoctoral Fellowships from the University of Hong Kong.
文摘This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson’s disease(PD).Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation,but as an integral part of this process,superoxides and other reactive oxygen species are also produced.Excessive free radical production contributes to oxidative stress.Cells have evolved to handle such stress via various endogenous anti-oxidant proteins.One such family of proteins is the mitochondrial uncoupling proteins(UCPs),which are anion carriers located in the mitochondrial inner membrane.There are five known homologues(UCP1 to 5),of which UCP4 and 5 are predominantly expressed in neural cells.In a series of previous publications,we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium(MPP+;toxic metabolite of MPTP)and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential,and reducing oxidative stress.We also showed how their expression can be influenced by nuclear factor kappa-B(NF-B)signaling pathway specifically in UCP4.Furthermore,we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin(hormone produced by adipocytes)acting via UCP2 against MPP+-induced toxicity.There is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with PD.Their expression,which can be induced,may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease.
文摘The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms.It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder.The advent of next generation sequencing(NGS)has allowed for a system-wide,unbiased approach to identify all gene variants in the genome simultaneously.With the plethora of new genes being identified,genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia(SCA),hereditary spastic paraplegia(HSP)and Charcot-Marie-Tooth disease(CMT)has become widely accepted.It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease(PD)and amyotrophic lateral sclerosis(ALS).The observation of pleiotropy has emerged,with mutations in the same gene giving rise to diverse phenotypes,which further increases the complexity of phenotype-genotype correlation.Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene,presence of modifier genes,and oligogenic inheritance.Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms,translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies,and ultimately finding disease-modifying therapies for neurodegenerative disorders.
基金the National Natural Science Foundation of China(81520108016,81661148045,and 31471084 to Yu-Feng Zang81671774 and 81630031 to Chao-Gan Yan+11 种基金81571228 to Tao Wu61571047 to Xia Wu81701664 to Jian Wang,81471654 to Biao Huang81701671 to Wei-Guo Liu82001898 to Xi-Ze Jia81771820,81371519 and 81571654 to Wei Luo)Henry G Leong Endowed Professorship in Neurology to Shu-Leong Ho and Shirley YY Pang,BRC for Mental Health at South London and Maudsley NHS Foundation Trust and by the Sackler Institute to Grainne McAlonan,NIH(2R01AG006457 to Fay B.Horak1RC4NS073008-01 and P50NS062684 to Tara Madhyastha)NINDS Intramural Research Program to Mark HallettStart-up Funds for Leading Talents at Beijing Normal UniversityNational Basic Science Data Center‘‘Chinese Data-sharing Warehouse for In-vivo Imaging Brain”(NBSDC-DB-15)to Xi-Nian ZuoGrant NU20-04-00294 of the Agency for Health Research,Czech Republic to Lenka Krajcovicova and Irena Rektorova。
文摘Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because of the large number of voxels in the brain,multiple comparison correction(MCC)must be performed to reduce false positive rates,and a smaller P value(usually including either liberal or stringent MCC)is widely recommended[1].
基金The authors’work is supported by the Henry G Leong Endowed Professorshipthe Donation Fund for Neurology Research,University of Hong Kong.
文摘There is a substantial amount of evidence from experimental parkinsonian models to show the neuroprotective effects of monoamine oxidase-B(MAOB)inhibitors.They have been studied for their potential disease-modifying effects in Parkinson’s disease(PD)for over 20 years in various clinical trials.This review provides a summary of the clinical trials and discusses the implications of their results in the context of disease-modification in PD.Earlier clinical trials on selegiline were confounded by symptomatic effects of this drug.Later clinical trials on rasagiline using delayed-start design provide newer insights in disease-modification in PD but success in achieving the aims of this strategy remain elusive due to obstacles,some of which may be insurmountable.
基金Tai Hung Fai Charitable Foundation-Edwin S H Leong Research Programme for Parkinson’s DiseaseThe Henry G.Leong Endowed Professorship in NeurologyThe Donation Fund for Neurology Research.
文摘Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.
基金Tai Hung Fai Charitable Foundation-Edwin S H Leong Research Programme for Parkinson’s DiseaseThe Henry G.Leong Endowed Professorship in Neurology+1 种基金The Donation Fund for Neurology ResearchHealth and Medical Research Fund(HMRF),Food and Health Bureau,Hong Kong S.A.R.
文摘Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarities between LRRK2-associated PD (LRRK2-PD) and sporadic PD, suggesting that LRRK2 is a potential disease modulator and a thera-peutic target in PD. LRRK2 mutant knock-in (KI) mouse models display subtle alterations in pathological aspects that mirror early-stage PD, including increased susceptibility of nigrostriatal neurotransmission, development of motor and non-motor symptoms, mitochondrial and autophagy-lysosomal defects and synucleinopathies. This review provides a rationale for the use of LRRK2 KI mice to investigate the LRRK2-mediated pathogenesis of PD and implications from current findings from different LRRK2 KI mouse models, and ultimately discusses the therapeutic potentials against LRRK2-associated pathologies in PD.