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Mechanisms of Neurodegeneration in Lewy Body Disorders

路易体疾病的神经变性机制

基本信息

批准号：
10112964
负责人：
Vivek Unni
金额：
$ 38.5万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112964
关键词：
Acidic Amino Acids Apoptosis Basic Science Biological Process Bleomycin Brain Breast C-terminal Cell Death Cells Cessation of life Chemicals Comet Assay Complex Cytoplasm DNA Double Strand Break DNA Repair Data Dementia with Lewy Bodies Disease Double Strand Break Repair Family member Fluorescence Microscopy Functional disorder Gamma synuclein Genetic Goals H2AFX gene Human Image Imaging Techniques Immunohistochemistry In Vitro Knock-out Knowledge Lead Lewy Bodies Lewy Body Disease Lewy body pathology Link Liquid substance Malignant Neoplasms Mediating Mus Mutation Names Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathway interactions Pharmacology Phase Play Poly(ADP-ribose) Polymerases Population Process Proteins Research Role Seeds Site Source Symptoms Synuclein Family System Testing Time Tissues Work alpha synuclein ataxia telangiectasia mutated protein brain cell disease diagnosis drug development human disease imaging approach in vitro Assay in vivo innovation loss of function malignant breast neoplasm melanoma mouse model multiphoton imaging neuron loss new therapeutic target novel novel therapeutic intervention protein function reconstitution recruit repair function repaired synucleinopathy

项目摘要

PROJECT SUMMARY One major obstacle to halting neurodegeneration in synucleinopathies like Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB) is a lack of understanding of why vulnerable cell populations die. Although aggregated alpha-synuclein Lewy pathology occurs within specific neurons, and their dysfunction or degeneration leads to symptoms in these diseases, how Lewy pathology itself plays a role is unclear. Recent work by the Unni lab has discovered a previously unrecognized function for the protein alpha-synuclein in repairing nuclear DNA double-strand breaks (DSB), by using newly developed in vivo multiphoton imaging techniques to study alpha-synuclein aggregation in mice. These approaches have now been extended (for the first time) to study DNA repair in living mouse brain. The unexpected function for alpha-synuclein immediately suggests an exciting new hypothesis for the role of aggregated alpha-synuclein Lewy inclusions in neurodegeneration. This central hypothesis is that in disease, alpha-synuclein protein is sequestered in cytoplasmic Lewy bodies, decreasing its nuclear DSB repair function and leading to cell death of Lewy body- containing neurons. Furthermore, it is proposed that the source of fibrillar α-synuclein that initially seeds Lewy body formation comes from dysregulated DSB repair. The preliminary data suggest this complex interrelationship, with alpha-synuclein aggregation causing dysregulated DSB repair and vice versa. Although completely novel, this link between alpha-synuclein and DSB repair could explain previously poorly understood associations between human and mouse mutations in the DSB repair protein Ataxia-Telangiectasia Mutated and alpha-synuclein aggregation, and between specific synuclein family members and cancer (e.g. alpha- synuclein & melanoma, gamma-synuclein & breast cancer). This proposal will use a combination of advanced imaging approaches in purified, reconstituted in vitro systems, in mouse brain in vivo, and in mouse & human (PD, DLB) fixed tissue to test how alpha-synuclein mediates DSB repair (Aim 1), how loss of nuclear α- synuclein function after cytoplasmic Lewy inclusion formation dysregulates DSB repair and contributes to neuronal cell death (Aim 2), and how dysregulated DSB repair can lead to Lewy inclusion formation (Aim 3). Overall, this project is innovative because it uses powerful, new in vivo experimental approaches to test a fundamentally new hypothesis for how alpha-synuclein aggregation into Lewy pathology is related to neurodegeneration. This contribution will be significant because it will provide a completely new set of targets for treating these debilitating neurodegenerative disorders that focuses on the DSB repair pathway, and because understanding alpha-synuclein-mediated DSB repair in detail will increase our basic science knowledge of this important biological process.

项目总结

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An Adaptive Role for DNA Double-Strand Breaks in Hippocampus-Dependent Learning and Memory.

DOI：
10.3390/ijms23158352
发表时间：
2022-07-28
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

Common cancer treatments targeting DNA double strand breaks affect long-term memory and relate to immediate early gene expression in a sex-dependent manner.

DOI：
10.18632/oncotarget.28180
发表时间：
2022
期刊：
Oncotarget
影响因子：
0
作者：
Boutros SW;Krenik D;Holden S;Unni VK;Raber J
通讯作者：
Raber J

Effects of Alpha-Synuclein Targeted Antisense Oligonucleotides on Lewy Body-Like Pathology and Behavioral Disturbances Induced by Injections of Pre-Formed Fibrils in the Mouse Motor Cortex.

DOI：
10.3233/jpd-212566
发表时间：
2021
期刊：
Journal of Parkinson's disease
影响因子：
0
作者：
Boutros SW;Raber J;Unni VK
通讯作者：
Unni VK

In vivo aggregation of presynaptic alpha-synuclein is not influenced by its phosphorylation at serine-129.

DOI：
10.1016/j.nbd.2021.105291
发表时间：
2021-05
期刊：
NEUROBIOLOGY OF DISEASE
影响因子：
6.1
作者：
Weston, Leah J.;Cook, Zoe T.;Stackhouse, Teresa L.;Sal, Mehtab K.;Schultz, Baergen I.;Tobias, Zachary J. C.;Osterberg, Valerie R.;Brockway, Nicole L.;Pizano, Saheli;Glover, Greta;Weissman, Tamily A.;Unni, Vivek K.
通讯作者：
Unni, Vivek K.

Infusion of etoposide in the CA1 disrupts hippocampal immediate early gene expression and hippocampus-dependent learning.