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Mechanisms Regulating Axonal Transport of ESCRT Machinery
Mechanisms Regulating Axonal Transport of ESCRT Machinery
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211153032
- ISBN
- 9798346740278
- DDC
- 574
- 서명/저자
- Mechanisms Regulating Axonal Transport of ESCRT Machinery
- 발행사항
- [Sl] : Columbia University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 130 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-05, Section: B.
- 주기사항
- Advisor: Waites, Clarissa L.
- 학위논문주기
- Thesis (Ph.D.)--Columbia University, 2024.
- 초록/해제
- 요약Turnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy and functional synapses. I recently showed that SV protein turnover is driven by neuronal activity in an endosomal sorting complex required for transport (ESCRT)-dependent manner. The ESCRT pathway comprises a series of protein complexes (ESCRT-0, I, II, III) that capture cargo and catalyze its sorting into multivesicular bodies (MVBs) for delivery to lysosomes. ESCRT-mediated protein degradation faces spatiotemporal challenges in neurons, as ESCRT components must undergo long-distance anterograde transport from soma to synapses in order to capture and sort cargo into MVBs. Moreover, MVBs and MVB-associated ESCRT-III proteins undergo retrograde transport back to the soma, where degradative lysosomes primarily reside. How ESCRT machinery is transported to and from synapses in morphologically complex neurons remains poorly understood. Here, I use live imaging approaches to characterize the axonal transport of ESCRT-0 protein Hrs and ESCRT-III protein CHMP2b, representing the initial and final components of the ESCRT pathway. In addition, I investigate the consequences of frontotemporal dementia (FTD)-causative mutant CHMP2bintron5 on CHMP2b axonal transport and synaptic localization. I find that Hrs is transported on a subset of Rab5+ early endosomes, and that neuronal activity stimulates the motility and synaptic delivery of these Hrs+ vesicles. Furthermore, I identify kinesin motor protein KIF13A as essential for the activity-dependent anterograde transport of Hrs to presynaptic boutons and the degradation of SV membrane proteins. While CHMP2b also undergoes activity-dependent transport to presynaptic sites, this transport is typically retrograde and associated with Rab7, suggesting that a large fraction of CHMP2b+ vesicles represent late endosomes undergoing transport from presynaptic terminals to the soma. In contrast, vesicles carrying the CHMP2bintron5 mutant exhibit aberrant oscillatory behavior reminiscent of a tug-of-war between motor proteins that disrupts their transport to presynaptic sites and contributes to defects in their maturation and activity-dependent transport. I demonstrate that these phenotypes are due in part to deficient binding of CHMP2bintron5 to kinesin binding protein (KBP), which I identify as a key regulator of CHMP2b axonal transport. Together, these data demonstrate a novel activity- and KIF13A-dependent mechanism for mobilizing axonal transport of ESCRT-0 machinery to initiate the degradation of SV membrane proteins, and shed light on the mechanisms of CHMP2b/MVB transport and the etiology of CHMP2bintron5-induced FTD.
- 일반주제명
- Biology
- 일반주제명
- Molecular biology
- 일반주제명
- Biochemistry
- 키워드
- Axonal transport
- 키워드
- Endosomes
- 키워드
- Synapses
- 기타저자
- Columbia University Neurobiology and Behavior
- 기본자료저록
- Dissertations Abstracts International. 86-05B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211153032
■006m o d
■007cr#unu||||||||
■020 ▼a9798346740278
■035 ▼a(MiAaPQ)AAI31636274
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aKirwan, Konner Roland.
■24510▼aMechanisms Regulating Axonal Transport of ESCRT Machinery
■260 ▼a[Sl]▼bColumbia University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a130 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-05, Section: B.
■500 ▼aAdvisor: Waites, Clarissa L.
■5021 ▼aThesis (Ph.D.)--Columbia University, 2024.
■520 ▼aTurnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy and functional synapses. I recently showed that SV protein turnover is driven by neuronal activity in an endosomal sorting complex required for transport (ESCRT)-dependent manner. The ESCRT pathway comprises a series of protein complexes (ESCRT-0, I, II, III) that capture cargo and catalyze its sorting into multivesicular bodies (MVBs) for delivery to lysosomes. ESCRT-mediated protein degradation faces spatiotemporal challenges in neurons, as ESCRT components must undergo long-distance anterograde transport from soma to synapses in order to capture and sort cargo into MVBs. Moreover, MVBs and MVB-associated ESCRT-III proteins undergo retrograde transport back to the soma, where degradative lysosomes primarily reside. How ESCRT machinery is transported to and from synapses in morphologically complex neurons remains poorly understood. Here, I use live imaging approaches to characterize the axonal transport of ESCRT-0 protein Hrs and ESCRT-III protein CHMP2b, representing the initial and final components of the ESCRT pathway. In addition, I investigate the consequences of frontotemporal dementia (FTD)-causative mutant CHMP2bintron5 on CHMP2b axonal transport and synaptic localization. I find that Hrs is transported on a subset of Rab5+ early endosomes, and that neuronal activity stimulates the motility and synaptic delivery of these Hrs+ vesicles. Furthermore, I identify kinesin motor protein KIF13A as essential for the activity-dependent anterograde transport of Hrs to presynaptic boutons and the degradation of SV membrane proteins. While CHMP2b also undergoes activity-dependent transport to presynaptic sites, this transport is typically retrograde and associated with Rab7, suggesting that a large fraction of CHMP2b+ vesicles represent late endosomes undergoing transport from presynaptic terminals to the soma. In contrast, vesicles carrying the CHMP2bintron5 mutant exhibit aberrant oscillatory behavior reminiscent of a tug-of-war between motor proteins that disrupts their transport to presynaptic sites and contributes to defects in their maturation and activity-dependent transport. I demonstrate that these phenotypes are due in part to deficient binding of CHMP2bintron5 to kinesin binding protein (KBP), which I identify as a key regulator of CHMP2b axonal transport. Together, these data demonstrate a novel activity- and KIF13A-dependent mechanism for mobilizing axonal transport of ESCRT-0 machinery to initiate the degradation of SV membrane proteins, and shed light on the mechanisms of CHMP2b/MVB transport and the etiology of CHMP2bintron5-induced FTD.
■590 ▼aSchool code: 0054.
■650 4▼aBiology
■650 4▼aMolecular biology
■650 4▼aBiochemistry
■653 ▼aAxonal transport
■653 ▼aEndosomes
■653 ▼aProtein degradation
■653 ▼aSynapses
■653 ▼aMultivesicular bodies
■690 ▼a0306
■690 ▼a0307
■690 ▼a0487
■71020▼aColumbia University▼bNeurobiology and Behavior.
■7730 ▼tDissertations Abstracts International▼g86-05B.
■790 ▼a0054
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17164693▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
