RISS 학술연구정보서비스

검색
다국어 입력

http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.

변환된 중국어를 복사하여 사용하시면 됩니다.

예시)
  • 中文 을 입력하시려면 zhongwen을 입력하시고 space를누르시면됩니다.
  • 北京 을 입력하시려면 beijing을 입력하시고 space를 누르시면 됩니다.
닫기
    인기검색어 순위 펼치기

    RISS 인기검색어

      Characterizing a Novel Metabolic Pathogenic Mechanism in Familial Hemiplegic Migraine.

      한글로보기

      https://www.riss.kr/link?id=T15933831

      • 저자
      • 발행사항

        Ann Arbor : ProQuest Dissertations & Theses, 2021

      • 학위수여대학

        Washington University in St. Louis Biology & Biomedical Sciences (Neurosciences)

      • 수여연도

        2021

      • 작성언어

        영어

      • 주제어
      • 학위

        Ph.D.

      • 페이지수

        174 p.

      • 지도교수/심사위원

        Advisor: Bonni, Azad.

      • 0

        상세조회
      • 0

        다운로드
      서지정보 열기
      • 내보내기
      • 내책장담기
      • 공유하기
      • 오류접수

      소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

      부가정보

      다국어 초록 (Multilingual Abstract)

      Migraine, an episodic neurological disorder, afflicts about 1 in 10 people at least monthly, yet the underlying pathophysiological mechanisms remain poorly understood. The prototypical monogenic migraine disorder, Familial Hemiplegic Migraine, theoretically presents an excellent opportunity for preclinical modeling, but thus far animal models of migraine have failed to recapitulate the severe migraine aura symptoms of episodic paralysis and ataxia. Mutations that cause Familial Hemiplegic Migraine occur in one of three genes, two neuronal ion channels, and interestingly, the astrocytic α2-Na/K ATPase. In the case of α2-Na/K ATPase, mutations primarily result in loss of protein function. As migraine is thought to be a disease of primarily neuronal hyperexcitability, it is unclear how a loss of α2-Na/K ATPase in astrocytes can confer hyperexcitability non-cell autonomously.To better characterize the sequelae stemming from loss of α2-Na/K ATPase in the brain, we generated α2-Na/K ATPase conditional knockout mice using an astrocyte-selective Cre driver. To our surprise, conditional knockout mice developed episodic paralysis and ataxia not unlike that seen in Familial Hemiplegic Migraine patients. Familial Hemiplegic Migraine motor symptoms present as part of the migraine aura, a set of neurological symptoms associated with a slow wave of synchronized neuronal activity followed by silence known as cortical spreading depression. Using widefield imaging of hemodynamics and neuronal activity via intrinsic optical signal and genetically encoded calcium indicators respectively, we discovered that unanaesthetized conditional knockout mice exhibit cortical spreading depression spontaneously at a similar frequency as paralysis bouts. Moreover, EEG abnormalities known as low voltage activity reliably accompanied cortical spreading depression. By recording continuous bilateral EEG activity in awake and behaving mice, we showed that low voltage activity is coincident with episodes of paralysis and ataxia. In sum, this data suggests that α2-Na/K ATPase conditional knockout mice model Familial Hemiplegic Migraine in an entirely novel way because they develop spontaneous migraine aura and associated motor symptoms.Next, we probed the pathogenic mechanisms of migraine in the conditional knockout mice by performing bulk and astrocyte-enriched RNA-Sequencing on cortex from mice prior to the onset of paralysis symptoms. From these studies, we discovered dysregulated metabolic pathways in the astrocytes, particularly in pathways related to amino acid metabolism. We next performed metabolomics and intersected the bioinformatics data with the metabolite levels. The metabolism network analysis revealed that serine, an uncharged, polar amino acid, is highly upregulated, as are the enzymes and other metabolites closely related to it in the network. Furthermore, HPLC verified that the levels of both enantiomers of serine, D- and L-, are significantly increased. D-serine is a particularly relevant amino acid to neurons because it serves as a co-agonist to the NMDA glutamate receptor, meaning that excess D-serine could theoretically confer neuronal hyperexcitability. We tested the hypothesis that excess serine contributes to the development of migraine aura motor symptoms in conditional knockout mice by implementing a diet with no serine or metabolically related amino acid glycine. Mass spectrometry verified that the serine/glycine free diet substantially lowered the levels of serine in the brain. Strikingly, conditional knockout mice on the serine/glycine free diet take nearly twice as long to develop paralysis symptoms, and symptoms are significantly less severe. Moreover, their motor function is significantly better for the duration of their lives that conditional knockout mice on the control diet. In sum, these studies suggest a novel metabolic pathogenic mechanism in Familial Hemiplegic Migraine. We anticipate that future studies will clarify mechanistic details driving serine buildup after astrocytic α2-Na/K ATPase loss and investigate the therapeutic potential of serine-lowering diets.
      번역하기

      Migraine, an episodic neurological disorder, afflicts about 1 in 10 people at least monthly, yet the underlying pathophysiological mechanisms remain poorly understood. The prototypical monogenic migraine disorder, Familial Hemiplegic Migraine, theore...

      Migraine, an episodic neurological disorder, afflicts about 1 in 10 people at least monthly, yet the underlying pathophysiological mechanisms remain poorly understood. The prototypical monogenic migraine disorder, Familial Hemiplegic Migraine, theoretically presents an excellent opportunity for preclinical modeling, but thus far animal models of migraine have failed to recapitulate the severe migraine aura symptoms of episodic paralysis and ataxia. Mutations that cause Familial Hemiplegic Migraine occur in one of three genes, two neuronal ion channels, and interestingly, the astrocytic α2-Na/K ATPase. In the case of α2-Na/K ATPase, mutations primarily result in loss of protein function. As migraine is thought to be a disease of primarily neuronal hyperexcitability, it is unclear how a loss of α2-Na/K ATPase in astrocytes can confer hyperexcitability non-cell autonomously.To better characterize the sequelae stemming from loss of α2-Na/K ATPase in the brain, we generated α2-Na/K ATPase conditional knockout mice using an astrocyte-selective Cre driver. To our surprise, conditional knockout mice developed episodic paralysis and ataxia not unlike that seen in Familial Hemiplegic Migraine patients. Familial Hemiplegic Migraine motor symptoms present as part of the migraine aura, a set of neurological symptoms associated with a slow wave of synchronized neuronal activity followed by silence known as cortical spreading depression. Using widefield imaging of hemodynamics and neuronal activity via intrinsic optical signal and genetically encoded calcium indicators respectively, we discovered that unanaesthetized conditional knockout mice exhibit cortical spreading depression spontaneously at a similar frequency as paralysis bouts. Moreover, EEG abnormalities known as low voltage activity reliably accompanied cortical spreading depression. By recording continuous bilateral EEG activity in awake and behaving mice, we showed that low voltage activity is coincident with episodes of paralysis and ataxia. In sum, this data suggests that α2-Na/K ATPase conditional knockout mice model Familial Hemiplegic Migraine in an entirely novel way because they develop spontaneous migraine aura and associated motor symptoms.Next, we probed the pathogenic mechanisms of migraine in the conditional knockout mice by performing bulk and astrocyte-enriched RNA-Sequencing on cortex from mice prior to the onset of paralysis symptoms. From these studies, we discovered dysregulated metabolic pathways in the astrocytes, particularly in pathways related to amino acid metabolism. We next performed metabolomics and intersected the bioinformatics data with the metabolite levels. The metabolism network analysis revealed that serine, an uncharged, polar amino acid, is highly upregulated, as are the enzymes and other metabolites closely related to it in the network. Furthermore, HPLC verified that the levels of both enantiomers of serine, D- and L-, are significantly increased. D-serine is a particularly relevant amino acid to neurons because it serves as a co-agonist to the NMDA glutamate receptor, meaning that excess D-serine could theoretically confer neuronal hyperexcitability. We tested the hypothesis that excess serine contributes to the development of migraine aura motor symptoms in conditional knockout mice by implementing a diet with no serine or metabolically related amino acid glycine. Mass spectrometry verified that the serine/glycine free diet substantially lowered the levels of serine in the brain. Strikingly, conditional knockout mice on the serine/glycine free diet take nearly twice as long to develop paralysis symptoms, and symptoms are significantly less severe. Moreover, their motor function is significantly better for the duration of their lives that conditional knockout mice on the control diet. In sum, these studies suggest a novel metabolic pathogenic mechanism in Familial Hemiplegic Migraine. We anticipate that future studies will clarify mechanistic details driving serine buildup after astrocytic α2-Na/K ATPase loss and investigate the therapeutic potential of serine-lowering diets.

      더보기

      분석정보

      View

      상세정보조회

      0

      Usage

      원문다운로드

      0

      대출신청

      0

      복사신청

      0

      EDDS신청

      0

      동일 주제 내 활용도 TOP

      더보기

      주제

      연도별 연구동향

      연도별 활용동향

      연관논문

      연구자 네트워크맵

      공동연구자 (7)

      유사연구자 (20) 활용도상위20명

      이 자료와 함께 이용한 RISS 자료

      나만을 위한 추천자료

      해외이동버튼