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
Background： Gaucher＇s disease （GD） is an autosomal recessive disorder caused by a deficiency of acid β-glucosidase （glucocerebrosidase [GBA]） that results in the accumulation of glucocerebroside within macropha...Background： Gaucher＇s disease （GD） is an autosomal recessive disorder caused by a deficiency of acid β-glucosidase （glucocerebrosidase [GBA]） that results in the accumulation of glucocerebroside within macrophages. Many mutations have been reported to be associated with this disorder. This study aimed to discover more mutations and provide data for the genetic pattern of the gene, which will help the development of quick and accurate genetic diagnostic tools for this disease. Methods： Genomic DNA was obtained from peripheral blood leukocytes of the patient and Sanger sequencing is used to sequence GBA gene. Sequence alignments of mammalian β-GBA （GCase） and three-dimensional protein structure prediction of the mutation were made. A construct of this mutant and its compound heterozygous counterpart were used to measure GCase in vitro. Results： GCase is relatively conserved at p.T219A. This novel mutation differs from its wild-type in structure. Moreover, it also causes a reduction in GCase enzyme activity. Conclusion： This novel mutation （c.655A〉G, p.T219A） is a pathogenic missense mutation, which contributes to GD.展开更多
Parkinson's disease(PD)is characterized by motor deficits and a wide variety of non-motor symptoms.The age of onset,rate of disease progression and the precise profile of motor and non-motor symptoms display consi...Parkinson's disease(PD)is characterized by motor deficits and a wide variety of non-motor symptoms.The age of onset,rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation.Neuropathologically,the loss of substantia nigra dopaminergic neurons is a key feature of PD.The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions,but there is also great variability in the neuropathology between individuals.While the dopamine replacement therapies can reduce motor symptoms,current therapies do not modify the disease progression.Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification.It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials,and that it is unlikely that a single treatment will be effective in all patients.Precision medicine,using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD,has been suggested as a way forward.PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk.In this review we assess current clinical trials targeting two enzymes,leucine-rich repeat kinase 2(LRRK2)and glucocerebrosidase(GBA),which are encoded by two most common PD risk genes.Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood,we ask if these precision medicinebased intervention strategies will prove"precise"or"personalized"enough to modify the disease process in PD patients.We also consider at what phases of the disease that such strategies might be effective,in light of the genes being primarily associated with the risk of developing disease in the first place,and less clearly linked to the rate of disease progression.Finally,we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider s展开更多
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This study was supported by grants from Natural Science Foundation of China （No. 81371269） and Shanghai Research Program （No. 14140902600, No. 2013ZYJB0015, and No. 14DJ 1400103）.
文摘Background： Gaucher＇s disease （GD） is an autosomal recessive disorder caused by a deficiency of acid β-glucosidase （glucocerebrosidase [GBA]） that results in the accumulation of glucocerebroside within macrophages. Many mutations have been reported to be associated with this disorder. This study aimed to discover more mutations and provide data for the genetic pattern of the gene, which will help the development of quick and accurate genetic diagnostic tools for this disease. Methods： Genomic DNA was obtained from peripheral blood leukocytes of the patient and Sanger sequencing is used to sequence GBA gene. Sequence alignments of mammalian β-GBA （GCase） and three-dimensional protein structure prediction of the mutation were made. A construct of this mutant and its compound heterozygous counterpart were used to measure GCase in vitro. Results： GCase is relatively conserved at p.T219A. This novel mutation differs from its wild-type in structure. Moreover, it also causes a reduction in GCase enzyme activity. Conclusion： This novel mutation （c.655A〉G, p.T219A） is a pathogenic missense mutation, which contributes to GD.
基金P.B.was supported by grants from the National Institutes of Health(1R01DC016519-01,5R21NS 093993-02,1R21 NS 106078-01A1)P.B.received additional awards from Office of the Assistant Secretary of Defense for Health Affairs(Parkinson's Research Program,Award No.W81XWH-17-1-0534)+1 种基金the Peter C.and Emajean Cook Foundation,which are outside but relevant to the submitted workZ.G.O.was supported by grants from the Michael J.Fox Foundation,the Canadian Consortium on Neurodegeneration in Aging(CCNA),the Canada First Research Excellence Fund(CFREF)from Parkinson Canada,awarded to McGill University for the Healthy Brains for Healthy Lives(HBHL)program.
文摘Parkinson's disease(PD)is characterized by motor deficits and a wide variety of non-motor symptoms.The age of onset,rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation.Neuropathologically,the loss of substantia nigra dopaminergic neurons is a key feature of PD.The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions,but there is also great variability in the neuropathology between individuals.While the dopamine replacement therapies can reduce motor symptoms,current therapies do not modify the disease progression.Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification.It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials,and that it is unlikely that a single treatment will be effective in all patients.Precision medicine,using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD,has been suggested as a way forward.PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk.In this review we assess current clinical trials targeting two enzymes,leucine-rich repeat kinase 2(LRRK2)and glucocerebrosidase(GBA),which are encoded by two most common PD risk genes.Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood,we ask if these precision medicinebased intervention strategies will prove"precise"or"personalized"enough to modify the disease process in PD patients.We also consider at what phases of the disease that such strategies might be effective,in light of the genes being primarily associated with the risk of developing disease in the first place,and less clearly linked to the rate of disease progression.Finally,we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider s
