Neuroacanthocytosis is an autosomal recessive or dominant inherited disease characterized by widespread, non-specific nervous system symptoms, or spiculated ＂acanthocytic＂ red blood cells. The clinical manifestation...Neuroacanthocytosis is an autosomal recessive or dominant inherited disease characterized by widespread, non-specific nervous system symptoms, or spiculated ＂acanthocytic＂ red blood cells. The clinical manifestations typically involve chorea and dystonia, or a range of other movement disorders. Psychiatric and cognitive symptoms may also be present. The two core neuroacanthocytosis syndromes, in which acanthocytosis is atypical, are autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome. Acanthocytes are found in a smaller proportion of patients with Huntington＇s disease-like 2 and pantothenate kinase-associated neurodegeneration. Because the clinical manifestations are diverse and complicated, in this review we present features of inheritance, age of onset, neuroimaging and laboratory findings, as well as the spectrum of central and peripheral neurological abnormalities and extraneuronal involvement to help distinguish the four specific syndromes.展开更多
Huntington＇s disease （HD） is a neurodegenera- tive disease caused by a polyglutamine expansion in the huntingtin （Htt） protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expressio...Huntington＇s disease （HD） is a neurodegenera- tive disease caused by a polyglutamine expansion in the huntingtin （Htt） protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 （SV2s）, a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic （TG） mice and Neuro2a mouse neuroblastoma cells （N2a cells） expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not signifi- cantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progres- sively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt- mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.展开更多
Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders,including Huntington disease[caused by expanded CAG repeats(CAGr)in the HTT gene],and amyotrophic lateral sclerosis[ALS...Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders,including Huntington disease[caused by expanded CAG repeats(CAGr)in the HTT gene],and amyotrophic lateral sclerosis[ALS,possibly caused by expanded GGGGCC repeats(G4C2r)in the C9ORF72 gene],of which the molecular mechanisms remain unclear.Here,we demonstrated that lowering the Drosophila homologue of tau protein(dtau)significantly rescued in vivo neurodegeneration,motor performance impairments,and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r.Expression of human tau(htau4 R)restored the disease-related phenotypes that had been mitigated by the loss of dtau,suggesting an evolutionarily-conserved role of tau in neurodegeneration.We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome-lysosome fusion,possibly due to lowering the level of BAG3,a regulator of autophagy and tau.Taken together,our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism.Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.展开更多
Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system,acting to mediate excitatory neurotransmission.However,high levels of glutamatergic input elicit excitotoxicity,contribut...Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system,acting to mediate excitatory neurotransmission.However,high levels of glutamatergic input elicit excitotoxicity,contribut-ing to neuronal cell death following acute brain injuries such as stroke and trauma.While excitotoxic cell death has also been implicated in some neurodegenerative disease models,the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration.Nevertheless,it is clear that excitatory synaptic dysregula-tion contributes to neurodegeneration,as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists.Here,we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease,Alzheimer’s disease,amyotrophic lateral sclerosis and Huntington’s disease.In contrast to classic excitotoxicity,emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration.We discuss mechanisms that regulate mitochondrial calcium uptake and release,the impact of LRRK2,PINK1,Parkin,beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters,and the role of autophagic mitochondrial loss in axodendritic shrinkage.Finally,we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix,thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss.While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems,a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.展开更多
文摘Neuroacanthocytosis is an autosomal recessive or dominant inherited disease characterized by widespread, non-specific nervous system symptoms, or spiculated ＂acanthocytic＂ red blood cells. The clinical manifestations typically involve chorea and dystonia, or a range of other movement disorders. Psychiatric and cognitive symptoms may also be present. The two core neuroacanthocytosis syndromes, in which acanthocytosis is atypical, are autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome. Acanthocytes are found in a smaller proportion of patients with Huntington＇s disease-like 2 and pantothenate kinase-associated neurodegeneration. Because the clinical manifestations are diverse and complicated, in this review we present features of inheritance, age of onset, neuroimaging and laboratory findings, as well as the spectrum of central and peripheral neurological abnormalities and extraneuronal involvement to help distinguish the four specific syndromes.
基金supported by the National Natural Science Foundation of China(81371417)
文摘Huntington＇s disease （HD） is a neurodegenera- tive disease caused by a polyglutamine expansion in the huntingtin （Htt） protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 （SV2s）, a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic （TG） mice and Neuro2a mouse neuroblastoma cells （N2a cells） expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not signifi- cantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progres- sively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt- mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.
基金the National Natural Science Foundation of China(81925012 and 31961130379)a Newton Advanced Fellowship(NAF_R1_191045)。
文摘Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders,including Huntington disease[caused by expanded CAG repeats(CAGr)in the HTT gene],and amyotrophic lateral sclerosis[ALS,possibly caused by expanded GGGGCC repeats(G4C2r)in the C9ORF72 gene],of which the molecular mechanisms remain unclear.Here,we demonstrated that lowering the Drosophila homologue of tau protein(dtau)significantly rescued in vivo neurodegeneration,motor performance impairments,and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r.Expression of human tau(htau4 R)restored the disease-related phenotypes that had been mitigated by the loss of dtau,suggesting an evolutionarily-conserved role of tau in neurodegeneration.We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome-lysosome fusion,possibly due to lowering the level of BAG3,a regulator of autophagy and tau.Taken together,our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism.Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.
文摘Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system,acting to mediate excitatory neurotransmission.However,high levels of glutamatergic input elicit excitotoxicity,contribut-ing to neuronal cell death following acute brain injuries such as stroke and trauma.While excitotoxic cell death has also been implicated in some neurodegenerative disease models,the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration.Nevertheless,it is clear that excitatory synaptic dysregula-tion contributes to neurodegeneration,as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists.Here,we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease,Alzheimer’s disease,amyotrophic lateral sclerosis and Huntington’s disease.In contrast to classic excitotoxicity,emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration.We discuss mechanisms that regulate mitochondrial calcium uptake and release,the impact of LRRK2,PINK1,Parkin,beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters,and the role of autophagic mitochondrial loss in axodendritic shrinkage.Finally,we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix,thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss.While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems,a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.
