Myelinosomes act as natural secretory organelles in Sertoli cells to prevent accumulation of aggregate-prone mutant Huntingtin and CFTR

Inappropriate deposition of insoluble aggregates of proteins with abnormal structures is a hallmark of affected organs in protein aggregation disease. Very rare, affected organs avoid aggregation naturally. This concerns atrophic testis in Huntington disease (HD). We aimed to understand how HD testi...

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Bibliographic Details
Published in:Human molecular genetics 2016-10, Vol.25 (19), p.4170-4185
Main Authors: Yefimova, Marina, Béré, Emile, Cantereau-Becq, Anne, Harnois, Thomas, Meunier, Annie-Claire, Messaddeq, Nadia, Becq, Frédéric, Trottier, Yvon, Bourmeyster, Nicolas
Format: Article
Language:English
Subjects:
Animals
Cystic Fibrosis Transmembrane Conductance Regulator / genetics
Humans
Huntingtin Protein / genetics
Huntington Disease / genetics
Huntington Disease / metabolism
Huntington Disease / pathology
Life Sciences
Male
Mice
Mice, Inbred CFTR
Mutant Proteins / genetics
Neurons / metabolism
Neurons / pathology
Organelles / genetics
Organelles / metabolism
Protein Aggregation, Pathological / genetics
Sertoli Cells / metabolism
Sertoli Cells / pathology
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Summary:Inappropriate deposition of insoluble aggregates of proteins with abnormal structures is a hallmark of affected organs in protein aggregation disease. Very rare, affected organs avoid aggregation naturally. This concerns atrophic testis in Huntington disease (HD). We aimed to understand how HD testis avoids aggregation. Using HD model R6/1 mice, we demonstrate that affected testis contain rare organelles myelinosomes. Myelinosomes secreted from testis somatic TM4 Sertoli cells provide the release of aggregate-prone mutant, but not normal Huntingtin (Htt) exon1. Myelinosomes also support the release of other aggregate-prone mutant protein responsible for cystic fibrosis (CF), F508delCFTR. The traffic and discharge of myelinosomes is facilitated by multivesicular bodies (MVB)s. Inhibition of MVB excretion induced reversible retention of both misfolded proteins inside TM4 Sertoli cells. We propose that myelinosome-mediated elimination of mutant proteins is an unusual secretory process allowing Sertoli cells getting rid of misfolded proteins to avoid aggregation and to maintain cell proteostasis.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddw251