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.

Gaide Chevronnay, Héloïse P.;Janssens, Virginie;Van Der Smissen, Patrick;Liao, X H;Courtoy, Pierre;et.al.
(2015) Endocrinology — Vol. 156, n° 6, p. 2349-2364 (2015)

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Abstract
Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which is impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin (CTNS). Cystinotic children develop subclinical 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 immunolabelling 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, GRP78 and PDI, associated with alternative XBP-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, ATF-4 and CHOP, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but LAMP-1 immunolabelling 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 show (i) compensated primary hypothyroidism and accelerated thyrocyte turnover; (ii) impaired Tg production linked to ER stress/UPR response; and (iii) altered endolysosomal trafficking and iodo-Tg processing. The Ctns(-/-) thyroid is useful to study disease progression and evaluate novel therapies.
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Gaide Chevronnay, H. P., Janssens, V., Van Der Smissen, P., Liao, X. H., Abid, Y., Nevo, N., Antignac, C., Refetoff, S., Cherqui, S., Pierreux, C., & Courtoy, P. (2015). 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. Endocrinology, 156(6), 2349-2364. https://doi.org/10.1210/en.2014-1672 (Original work published 2015)