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Curr Biol. 2017 Dec 4;27(23):3626-3642.e6. doi: 10.1016/j.cub.2017.10.054. Epub 2017 Nov 22.

Stall in Canonical Autophagy-Lysosome Pathways Prompts Nucleophagy-Based Nuclear Breakdown in Neurodegeneration.

Author information

1
Department of Basic and Clinical Neuroscience, King's College London, 125 Coldharbour Lane, SE5 9NU London, UK.
2
Department of Clinical Genetics and Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands; Department of Functional Genome Analysis, VU University, Amsterdam, the Netherlands.
3
Centre for Ultrastructural Imaging, King's College London, SE1 1UL London, UK.
4
Department Medical and Molecular Genetics, School of Basic and Biomedical Sciences, King's College London, SE1 9RT London, UK.
5
Department of Basic and Clinical Neuroscience, King's College London, 125 Coldharbour Lane, SE5 9NU London, UK; Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK; Randall Division for Cell and Molecular Biophysics, Muscle Signaling Section, King's College London, London, UK.
6
Department Medical and Molecular Genetics, School of Basic and Biomedical Sciences, King's College London, SE1 9RT London, UK; Sobell Department of Motor Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK.
7
Department of Basic and Clinical Neuroscience, King's College London, 125 Coldharbour Lane, SE5 9NU London, UK. Electronic address: manolis.fanto@kcl.ac.uk.

Abstract

The terminal stages of neuronal degeneration and death in neurodegenerative diseases remain elusive. Autophagy is an essential catabolic process frequently failing in neurodegeneration. Selective autophagy routes have recently emerged, including nucleophagy, defined as degradation of nuclear components by autophagy. Here, we show that, in a mouse model for the polyglutamine disease dentatorubral-pallidoluysian atrophy (DRPLA), progressive acquirement of an ataxic phenotype is linked to severe cerebellar cellular pathology, characterized by nuclear degeneration through nucleophagy-based LaminB1 degradation and excretion. We find that canonical autophagy is stalled in DRPLA mice and in human fibroblasts from patients of DRPLA. This is evidenced by accumulation of p62 and downregulation of LC3-I/II conversion as well as reduced Tfeb expression. Chronic autophagy blockage in several conditions, including DRPLA and Vici syndrome, an early-onset autolysosomal pathology, leads to the activation of alternative clearance pathways including Golgi membrane-associated and nucleophagy-based LaminB1 degradation and excretion. The combination of these alternative pathways and canonical autophagy blockade, results in dramatic nuclear pathology with disruption of the nuclear organization, bringing about terminal cell atrophy and degeneration. Thus, our findings identify a novel progressive mechanism for the terminal phases of neuronal cell degeneration and death in human neurodegenerative diseases and provide a link between autophagy block, activation of alternative pathways for degradation, and excretion of cellular components.

KEYWORDS:

Atrophin-1; EPG5; autophagy; neurodegeneration; nucleophagy; polyglutamine

PMID:
29174892
PMCID:
PMC5723708
DOI:
10.1016/j.cub.2017.10.054
[Indexed for MEDLINE]
Free PMC Article

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