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The Deleterious Duo of Neurodegeneration: Lysosomes and Mitochondria

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Mitochondrial Dysfunction in Neurodegenerative Disorders

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Abstract

Many studies have demonstrated that the accumulation of aggregate-prone proteins due to defects in cellular quality control systems contributes to the development of neurodegenerative diseases. One form of quality control within neurons is autophagy, an intracellular pathway involved in the breakdown of cytosolic constituents. Lysosomes mediate autophagy, and their dysfunction may contribute to perturbations in cellular homeostasis and affect other organelles such as mitochondria. Mitochondrial malfunction may then further perpetuate lysosomal damage and initiate inflammatory responses. Therefore, lysosomes and mitochondria share a reciprocal relationship where dysfunction in one often affects the function of the other. These consequences of lysosome and mitochondrial impairment complete a deleterious feedback loop that concludes not only in neurodegeneration but also neuroinflammation. Herein, we discuss the primary types of autophagy and their underlying mechanisms, the regulation of lysosomal biogenesis and function, and the link between lysosomal and mitochondrial dysfunction. We conclude this chapter by assessing the role of lysosomal dysfunction in neurodegenerative diseases.

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Acknowledgments

We thank Julia Feckes for the assistance in drafting Fig. 12.1 and the Laboratory of Pathology of the National Cancer Institute for the images in Fig. 12.2. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute.

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Authors and Affiliations

  1. National Institutes of Health, Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA

    Matthew Nguyen BS & Wendy Westbroek PhD

  2. Section of Molecular Neurogenetics, National Institutes of Health, Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA

    Ellen Sidransky MD

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  1. Matthew Nguyen BS
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Correspondence to Ellen Sidransky MD .

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  1. Newcastle University Medical School, Well. Trust Ctr. for Mitochondrial Res., Newcastle upon Tyne, United Kingdom

    Amy K. Reeve

  2. Newcastle University Medical School, Well. Trust Ctr. for Mitochondrial Res., Newcastle upon Tyne, United Kingdom

    Eve M. Simcox

  3. Cell and Developmental Biology, University College London, London, United Kingdom

    Michael R. Duchen

  4. Newcastle University Medical School, Well. Trust Ctr. for Mitochondrial Res., Newcastle upon Tyne, United Kingdom

    Doug M. Turnbull

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Nguyen, M., Sidransky, E., Westbroek, W. (2016). The Deleterious Duo of Neurodegeneration: Lysosomes and Mitochondria. In: Reeve, A., Simcox, E., Duchen, M., Turnbull, D. (eds) Mitochondrial Dysfunction in Neurodegenerative Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-28637-2_12

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