Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons.

Autor:	Chua JP; Department of Neurology, Johns Hopkins Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: jchua6@jhmi.edu., Bedi K; Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA., Paulsen MT; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI, USA., Ljungman M; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI, USA., Tank EMH; Department of Neurology, University of Michigan, Ann Arbor, MI, USA., Kim ES; Department of Neurology, University of Michigan, Ann Arbor, MI, USA., McBride JP; Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI, USA., Colón-Mercado JM; National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA., Ward ME; National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA., Weisman LS; Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA., Barmada SJ; Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
Jazyk:	angličtina
Zdroj:	Current biology : CB [Curr Biol] 2022 Jun 20; Vol. 32 (12), pp. 2581-2595.e6. Date of Electronic Publication: 2022 May 16.
DOI:	10.1016/j.cub.2022.04.053
Abstrakt:	Autophagy is a conserved, multi-step process of capturing proteolytic cargo in autophagosomes for lysosome degradation. The capacity to remove toxic proteins that accumulate in neurodegenerative disorders attests to the disease-modifying potential of the autophagy pathway. However, neurons respond only marginally to conventional methods for inducing autophagy, limiting efforts to develop therapeutic autophagy modulators for neurodegenerative diseases. The determinants underlying poor autophagy induction in neurons and the degree to which neurons and other cell types are differentially sensitive to autophagy stimuli are incompletely defined. Accordingly, we sampled nascent transcript synthesis and stabilities in fibroblasts, induced pluripotent stem cells (iPSCs), and iPSC-derived neurons (iNeurons), thereby uncovering a neuron-specific stability of transcripts encoding myotubularin-related phosphatase 5 (MTMR5). MTMR5 is an autophagy suppressor that acts with its binding partner, MTMR2, to dephosphorylate phosphoinositides critical for autophagy initiation and autophagosome maturation. We found that MTMR5 is necessary and sufficient to suppress autophagy in iNeurons and undifferentiated iPSCs. Using optical pulse labeling to visualize the turnover of endogenously encoded proteins in live cells, we observed that knockdown of MTMR5 or MTMR2, but not the unrelated phosphatase MTMR9, significantly enhances neuronal degradation of TDP-43, an autophagy substrate implicated in several neurodegenerative diseases. Our findings thus establish a regulatory mechanism of autophagy intrinsic to neurons and targetable for clearing disease-related proteins in a cell-type-specific manner. In so doing, our results not only unravel novel aspects of neuronal biology and proteostasis but also elucidate a strategy for modulating neuronal autophagy that could be of high therapeutic potential for multiple neurodegenerative diseases. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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