자료유형  

 학위논문

Control Number  

0016935062

International Standard Book Number  

9798380848138

Dewey Decimal Classification Number  

616

Main Entry-Personal Name  

Neel, Dylan V.

Publication, Distribution, etc. (Imprint  

[S.l.] : Harvard University., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(171 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-05, Section: B.

General Note  

Advisor: Chiu, Isaac.

Dissertation Note  

Thesis (Ph.D.)--Harvard University, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons, and that GSDME plays a critical role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase dependent GSDME cleavage and rapid localization to mitochondria in axonal processes, where GSDME promoted mitochondrial depolarization, trafficking defects along axons, and neurite retraction. Expression of activated N-GSDME in primary neurons was sufficient to drive mitochondrial dysfunction, neurite loss and cell death. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 also induced GSDME activation and mediated damage to mitochondria and neurite loss; knockout of GSDME in primary mouse neurons was protective. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Lastly, knockout of GSDME in the mutant SOD1G93A mouse model of ALS prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammatory markers. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that contributes to neurodegeneration.

Subject Added Entry-Topical Term  

Neurosciences.

Subject Added Entry-Topical Term  

Immunology.

Subject Added Entry-Topical Term  

Biology.

Index Term-Uncontrolled  

Cell death

Index Term-Uncontrolled  

Mitochondrial dysfunction

Index Term-Uncontrolled  

Neurodegeneration

Index Term-Uncontrolled  

Central nervous system

Index Term-Uncontrolled  

Frontotemporal dementia

Added Entry-Corporate Name  

Harvard University Medical Sciences

Host Item Entry  

Dissertations Abstracts International. 85-05B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:643440