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.