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Engineering therapeutic TRIM11 disaggregases for Alzheimer's Disease-Related Dementias (ADRDs)

工程治疗 TRIM11 解聚酶治疗阿尔茨海默病相关痴呆症 (ADRD)

基本信息

批准号：
10539674
负责人：
James Shorter
金额：
$ 44.69万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10539674
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease related dementia Amino Acid Motifs Amyloid Amyloid Fibrils Amyotrophic Lateral Sclerosis Autopsy Biological Assay Biotechnology Cytoplasmic Inclusion Directed Molecular Evolution Disease Engineering Family Frontotemporal Dementia Human Human Engineering Huntington Disease In Vitro Lewy Bodies Lewy Body Dementia Libraries Mediating Methods Modeling Movement Disorders Multiple System Atrophy Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Parkinson Disease Pathologic Patients Persons Pharmacologic Substance Proteins Research Structure TRIM Motif TRIM11 gene Therapeutic Therapeutic Agents Toxic effect Validation Variant Yeasts alpha synuclein conformer effective therapy in vivo member mutant neuroprotection neurotoxic novel presynaptic prevent protein misfolding proteostasis synucleinopathy therapeutically effective yeast genetics

项目摘要

Project Summary Our research objective is to engineer variants of a human tripartite motif (TRIM) protein, TRIM11, with enhanced ability to mitigate alpha-synuclein (alpha-syn) misfolding and toxicity that underlies synucleinopathies. Synucleinopathies are common, debilitating neurodegenerative disorders that afflict millions of people worldwide and include Parkinson's Disease, Multiple System Atrophy and Lewy Body Dementia, an Alzheimer's Disease-Related Dementia [ADRD]). In all synucleinopathies, the proteostasis network fails to counter the misfolding of the small presynaptic protein alpha-syn. alpha-Syn populates a range of misfolded conformers ranging from soluble toxic oligomers to self-templating amyloid fibrils capable of initiating and propagating disease de novo. alpha-Syn fibrils cluster into large cytoplasmic inclusions termed Lewy Bodies, a pathological hallmark of synucleinopathies. Unfortunately, there are no effective therapeutics for synucleinopathies. Remarkably, we have discovered that human TRIM11 can prevent and reverse the formation of alpha-syn fibrils and reduce their toxicity in vitro and in vivo. However, we suspect that TRIM11 becomes overwhelmed and fails to counter alpha-syn misfolding in synucleinopathies. Indeed, elevating expression of TRIM11 partially mitigates alpha-syn-mediated neurodegeneration in vivo, but neuroprotection is incomplete and significant neurodegeneration still occurs. Thus, methods to enhance TRIM11 disaggregase activity in the degenerating neurons of synucleinopathy patients could reverse deleterious accumulation of alpha-syn and offer a solution for synucleinopathies. We hypothesize that engineering TRIM11 with enhanced disaggregase activity will enable more effective disassembly of toxic oligomeric and amyloid forms of alpha-syn, which could confer therapeutic benefits in synucleinopathies. Thus, we will engineer TRIM11 with enhanced disaggregase activity against neurotoxic alpha-syn conformers. We will then assess the ability of these enhanced TRIM11 variants to antagonize alpha-syn aggregation and toxicity elicited by alpha-syn oligomers and fibrils in mammalian primary neurons. To do so, we will pursue three aims: (1) Engineer enhanced TRIM11 variants to mitigate alpha-syn aggregation and toxicity in yeast; (2) Define optimal TRIM11 variants that disassemble alpha-syn fibrils and oligomers in vitro; and (3) Define enhanced TRIM11 variants that mitigate alpha-syn aggregation and toxicity in primary neurons. The proposed project establishes a pipeline that begins by leveraging the power of yeast genetics to pinpoint optimal TRIM11 disaggregases from mutant libraries and culminates with their validation at the pure protein level and in mammalian neurons. By the end of these studies, there will be a clear “go/no go” decision for moving enhanced TRIM11 variants into mouse synucleinopathy models and ultimately synucleinopathy patients. Moreover, by revealing how TRIM11 disaggregase activity can be enhanced by specific mutations we will begin to clarify the mechanism of TRIM11 action.

项目总结