Mechanistic investigation of in vivo pathways of neuronal mitochondrial degradation

项目摘要/摘要 神经元是体内能量要求最高的细胞类型之一，因此，严重依赖于 线粒体的输出为它们的基本功能提供燃料。正因为如此，过多的基因 其功能障碍与神经退行性疾病有关，与线粒体功能有关。的 线粒体的降解过程对神经元的健康和生存尤为重要。尽管如此 LINK，对于介导神经元线粒体崩溃的细胞生物学途径知之甚少 在他们的神经组织中的自然生理环境中。这项建议的总体目标是获得 进一步了解神经元用来分解线粒体的各种途径。 在神经组织中，神经元得到一种被称为神经胶质细胞的特殊细胞类型的支持。最近是这样的 研究发现，共济失调相关基因Vps13D的敲除会导致对 神经元通过一种称为有丝分裂的途径分解线粒体的能力。作为对这一强势的回应 抑制，神经元自适应地诱导另一种线粒体破坏方式，涉及 将受损的线粒体转移到支持性神经胶质细胞，使其最终降解。随着发现了 这种线粒体降解的新途径，本提案的指导阶段将使用健壮的 与Vps13D缺失相关的表型以指导研究非细胞自主的工具的开发 体内神经元中线粒体的降解。这项工作还将揭示导致 诱导这种跨细胞神经元导致神经胶质细胞线粒体崩溃。 在该提案的独立阶段，目标将是使用这些新开发的工具来获得 对线粒体如何从神经元中释放的机械性理解。使用强大的基因工具 在果蝇研究中，这一目标将测试具有细胞间调节历史的候选分子。 线粒体在其他细胞类型中的运输以确定它们是否参与神经元到胶质细胞 线粒体转移。 最后，该提案在独立阶段的另一个重点的目标将是确定这一点是否 新发现的另一种形式的线粒体降解在 随着自噬水平的降低，衰老的过程。然后，这个目标将测试细胞和功能 在这一老年易感人群中干扰线粒体神经元到神经胶质细胞的转移的后果 神经元。 在完成本申请书中建议的研究后，申请人将制定出一份 专注于跨细胞线粒体细胞生物学的独立研究生涯的独特利基 神经元的退化。

Project Summary/Abstract Neurons are among the most energetically-demanding cell types in the body, and as such, heavily rely on the output of mitochondria to fuel their basic functionality. Because of this, a disproportionate number of genes whose dysfunction is associated with neurodegenerative disease are related to mitochondrial function. Of particular importance to neuronal health and survival is the process of degrading mitochondria. Despite this link, little is known about the cell biological pathways that mediate the breakdown of mitochondria in neurons within their native, physiological environment in nervous tissue. The overall goal of this proposal is gain a further understanding of the various pathways neurons utilize to break down their mitochondria. Within nervous tissue, neurons get support from a specialized cell type known as glial cells. It has recently been discovered that knock down of the ataxia-associated gene Vps13D leads to the strong inhibition of a neuron’s ability to break down their mitochondria via a pathway known as mitophagy. In response to this robust inhibition, neurons adaptively induce an alternative means of mitochondrial breakdown that involves the transfer of damaged mitochondria to supportive glial cells for their ultimate degradation. With the discovery of this new pathway of mitochondrial degradation, the mentored phase of this proposal will use the robust phenotype associated with loss of Vps13D to guide the development of tools for studying non-cell autonomous mitochondrial degradation in neurons in vivo. This work will also uncover the conditions that lead to the induction of this transcellular neuron to glia mitochondrial breakdown. In the independent phase of this proposal, the goal will be to use these newly developed tools to gain a mechanistic understanding of how mitochondria are released from neurons. Using the powerful genetic tools available in fruit fly research, this Aim will test out candidate molecules with a history of mediating intercellular mitochondrial trafficking in other cell types to determine whether they participate in neuron to glial mitochondrial transfer. Finally, the goal of the another focus of this proposal in the independent phase will be to determine if this newly discovered, alternative form of mitochondrial degradation become adaptively more prevalent during the course of aging as levels of autophagy decrease. Then, this Aim will test the cellular and functional consequences of disrupting neuron-to-glial transfer of mitochondrial in this susceptible population of aged neurons. With the completion of the research proposed in this application, the applicant will have carved out a distinctive niche for an independent research career focusing on the cell biology of transcellular mitochondrial degradation in neurons.