title: A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing.
abstract: Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which are impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin. Cystinotic children develop subclinical and then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns(-/-) mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (∼4-fold). By histology, hyperplasia and hypertrophy of most follicles preceded colloid exhaustion. Increased immunolabeling for thyrocyte proliferation and apoptotic shedding indicated accelerated cell turnover. Electron microscopy revealed endoplasmic reticulum (ER) dilation, apical lamellipodia indicating macropinocytic colloid uptake, and lysosomal cystine crystals. Tg accumulation in dilated ER contrasted with mRNA down-regulation. Increased expression of ER chaperones, glucose-regulated protein of 78 kDa and protein disulfide isomerase, associated with alternative X-box binding protein-1 splicing, revealed unfolded protein response (UPR) activation by ER stress. Decreased Tg mRNA and ER stress suggested reduced Tg synthesis. Coordinated increase of UPR markers, activating transcription factor-4 and C/EBP homologous protein, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but lysosome-associated membrane protein-1 immunolabeling disclosed enlarged vesicles containing iodo-Tg and impaired lysosomal fusion. Isopycnic fractionation showed iodo-Tg accumulation in denser lysosomes, suggesting defective lysosomal processing and hormone release. In conclusion, Ctns(-/-) mice showed the following alterations: 1) compensated primary hypothyroidism and accelerated thyrocyte turnover; 2) impaired Tg production linked to ER stress/UPR response; and 3) altered endolysosomal trafficking and iodo-Tg processing. The Ctns(-/-) thyroid is useful to study disease progression and evaluate novel therapies.
authors: Cell Biology Unit (H.P.G.C., V.J., P.V.D.S., Y.A., C.E.P., P.J.C.), de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium; Departments of Medicine (X.H.L., S.R.) and Pediatrics and Genetics (S.R), The University of Chicago, Chicago, Illinois 60637; INSERM, Unité 1163 (N.N., C.A.), Hôpital Necker-Enfants Malades and Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France; and Department of Pediatrics (S.C.), Division of Genetics, University of California, San Diego, San Diego, California 92161.
authors: H P
authors: HP
authors: Gaide Chevronnay
authors: V
authors: V
authors: Janssens
authors: P
authors: P
authors: Van Der Smissen
authors: X H
authors: XH
authors: Liao
authors: Y
authors: Y
authors: Abid
authors: N
authors: N
authors: Nevo
authors: C
authors: C
authors: Antignac
authors: S
authors: S
authors: Refetoff
authors: S
authors: S
authors: Cherqui
authors: C E
authors: CE
authors: Pierreux
authors: P J
authors: PJ
authors: Courtoy
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003554:Cystinosis / Q000378:metabolism* / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D013954:Thyroglobulin / Q000096:biosynthesis*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C534463:cystinosin protein, mouse; D013954:Thyroglobulin