Investigating the role of neuronal SYNJ2 in mRNA transport and mitochondrial function

研究神经元 SYNJ2 在 mRNA 转运和线粒体功能中的作用

• 批准号: 10747226
• 负责人: Whitney Sharee Gibbs
• 金额: $ 5.2万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10747226
• 关键词: Advisory Committees; Alzheimer' s Disease; Axon; Back; Cell Differentiation process; Cells; Complex; Dendrites; Disease; Distal; Distant; Ensure; Goals; Half-Life; Health; Heterogeneity; Homeostasis; Human; Huntington Disease; Laboratories; Maintenance; Mediating; Membrane; Mentors; Messenger RNA; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Mutate; Nerve Degeneration; Neurons; PINK1 gene; Parkinson Disease; Pathologic; Peripheral; Phase; Phosphotransferases; Physiological; Play; Process; Protein Biosynthesis; Proteins; RNA Binding; RNA Recognition Motif; Research; Role; SYNJ1 gene; Surface; Training; Transcript; Translations; Travel; Work; axon regeneration; axonal degeneration; career; diversity and inclusion; in vivo regeneration; innovation; meter; mitochondrial messenger RNA; neuronal cell body; neurotransmission; preservation

Project Summary Neurons critically depend on mitochondria function to maintain membrane excitability and execute complex functions, such as neurotransmission and plasticity. Neurons are highly differentiated cells that require large amounts of ATP to perform these functions and ensure long-term viability. The unique complexity of neurons is reflected by the extremely long segments that can extend up to a meter long and the functional heterogeneity for each neuronal compartment. The neuron has specialized mechanisms to transport mitochondria to the most distal parts to maintain proper neuronal function and survival. In turn, peripheral mitochondria rely on the transport of cellular components, such as mRNA and proteins, to sustain mitochondrial homeostasis without the need to travel back to the soma. The current proposal focuses on this aspect of mitochondrial maintenance, mitochondrial transcripts' ability to be trafficked to the axons for local translation, and how this influences mitochondrial and neuronal health and function. This project's significance is focused on PINK1, an essential mitochondrial kinase that is mutated in a hereditable form of Parkinson's disease. PINK1 protein will not survive transport down the axon because of its short half-life. To this end, our laboratory described an innovative mechanism by which mitochondria carry PINK1 mRNA on its surface to axons. Synaptojanin 2 (SYNJ2) was found to be responsible for tethering PINK1 mRNA to the mitochondria for axonal localization and local protein synthesis. The study of this neuronal-specific model suggests that the RNA binding function of SYNJ2 is required for PINK1-mediated processes (such as mitophagy); however, this has yet to be explored. The work planned in this proposal will explore the physiological and pathological consequence of disrupting the RNA binding function of SYNJ2, and; this unique approach is of critical importance for understanding mitochondrial mRNA transport and translation for preserving mitochondrial health. Thus, I hypothesize that Hypothesis: The RNA Recognition Motif of SYNJ2 causes PINK1 mRNA to colocalize with and be transported with mitochondria in a manner critical for PINK1 functions in axons and dendrites and thereby for maintaining neuronal health. I have assembled an advisory committee to provide conceptual and technical guidance as I explore the following Specific Aims: Aim 1: Examine the function of endogenous SYNJ2 and its RNA recognition motif in mice. Aim 2: Establish the role of peripheral SYNJ2 in mediating axonal mitochondrial function and neuronal health Aim 3: Investigate the impact of SYNJ2 RNA binding function in modulating axonal degeneration and regeneration in vivo. I have also developed a tailored diversity and inclusion training plan to execute during the mentored phase. The proposed studies and mentoring plans described in this proposal will provide me with a robust training platform to launch my independent academic research career.

Project Summary Neurons critically depend on mitochondria function to maintain membrane excitability and execute complex functions, such as neurotransmission and plasticity. Neurons are highly differentiated cells that require large amounts of ATP to perform these functions and ensure long-term viability. The unique complexity of neurons is reflected by the extremely long segments that can extend up to a meter long and the functional heterogeneity for each neuronal compartment. The neuron has specialized mechanisms to transport mitochondria to the most distal parts to maintain proper neuronal function and survival. In turn, peripheral mitochondria rely on the transport of cellular components, such as mRNA and proteins, to sustain mitochondrial homeostasis without the need to travel back to the soma. The current proposal focuses on this aspect of mitochondrial maintenance, mitochondrial transcripts' ability to be trafficked to the axons for local translation, and how this influences mitochondrial and neuronal health and function. This project's significance is focused on PINK1, an essential mitochondrial kinase that is mutated in a hereditable form of Parkinson's disease. PINK1 protein will not survive transport down the axon because of its short half-life. To this end, our laboratory described an innovative mechanism by which mitochondria carry PINK1 mRNA on its surface to axons. Synaptojanin 2 (SYNJ2) was found to be responsible for tethering PINK1 mRNA to the mitochondria for axonal localization and local protein synthesis. The study of this neuronal-specific model suggests that the RNA binding function of SYNJ2 is required for PINK1-mediated processes (such as mitophagy); however, this has yet to be explored. The work planned in this proposal will explore the physiological and pathological consequence of disrupting the RNA binding function of SYNJ2, and; this unique approach is of critical importance for understanding mitochondrial mRNA transport and translation for preserving mitochondrial health. Thus, I hypothesize that Hypothesis: The RNA Recognition Motif of SYNJ2 causes PINK1 mRNA to colocalize with and be transported with mitochondria in a manner critical for PINK1 functions in axons and dendrites and thereby for maintaining neuronal health. I have assembled an advisory committee to provide conceptual and technical guidance as I explore the following Specific Aims: Aim 1: Examine the function of endogenous SYNJ2 and its RNA recognition motif in mice. Aim 2: Establish the role of peripheral SYNJ2 in mediating axonal mitochondrial function and neuronal health Aim 3: Investigate the impact of SYNJ2 RNA binding function in modulating axonal degeneration and regeneration in vivo. I have also developed a tailored diversity and inclusion training plan to execute during the mentored phase. The proposed studies and mentoring plans described in this proposal will provide me with a robust training platform to launch my independent academic research career.