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.
Pubmed ID: 29174892 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.
View all literature mentionsNon-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.
View all literature mentionsCommercial antibody vendor which supplies antibodies and other products to life science researchers.
View all literature mentionsMus musculus with name C57BL/6J-Tg(CAG-GFP/LC3/RFP/LC3*deltaG)2Nmz from IMSR.
View all literature mentionsThis polyclonal targets MAP2 antibody - Neuronal Marker
View all literature mentionsThis monoclonal targets α-Tubulin
View all literature mentionsThis polyclonal targets Phospho-p70 S6 Kinase (Thr389)
View all literature mentionsThis unknown targets ATG13 phospho S318 Antibody
View all literature mentionsThis monoclonal targets Histone H2A.X pSer139
View all literature mentionsThis monoclonal targets Mouse Drosophila Lamin Dm0
View all literature mentionsThis monoclonal targets Polyglutamine-Expansion Diseases Marker clone 5TF1-1C2
View all literature mentionsThis monoclonal targets GM130
View all literature mentionsThis polyclonal targets LMNB1
View all literature mentionsThis monoclonal targets p62/SQSTM1
View all literature mentionsThis polyclonal targets Human LAMP2a - Lysosome Marker
View all literature mentionsDrosophila melanogaster with name w[*]; P{w[+mC]=UAS-lacZ.Exel}2 from BDSC.
View all literature mentionsCell line SK-N-BE(2) is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name C3;B6-Tg(Prnp-ATN1)150Dbo/Mmmh from MMRRC.
View all literature mentionsMus musculus with name C3;B6-Tg(Prnp-ATN1)84Dbo/Mmmh from MMRRC.
View all literature mentions