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bioRxiv · 10.1101/2022.08.17.504300

A PATHWAY FOR T3 SIGNALING IN THE BRAIN TO IMPROVE THE VARIABLE EFFECTIVENESS OF THERAPY WITH L-T4

Salas-Lucia, F.·Fekete, C.·Sinko, R.·Egri, P.·Rada, K.·Ruska, Y.·Bocco, B.·Fonseca, T. L.·Gereben, B.·Bianco, A. C.
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Abstract

The effectiveness of therapy for hypothyroidism with levothyroxine (L-T4) depends on patients ability to activate T4 to T3 --altered in carriers of a common deiodinase polymorphism (Thr92Ala-DIO2). Some patients that exhibit impaired mood and cognition improve with liothyronine (L-T3), but the underlying mechanisms remain unknown. Here we show that the T3-indicator mouse carrying the Thr92Ala-DIO2 polymorphism exhibits a hippocampal-specific reduction in T3 activation and signaling that limits the effectiveness of L-T4 therapy. To understand the L-T3 effect, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering relatively large amounts of T3 to the cell nucleus, doubling the expression of the T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and the type 3 deiodinase (Dio3), which transports and inactivates T3, respectively. Notwithstanding, T3 gets away from degradation because D3 active center is in the cytosol. These findings provide (i) a basis for the variable effectiveness of L-T4 therapy, (ii) a pathway for L-T3 to reach neurons, and (iii) resolve the paradox of T3 signaling in the brain amid high D3 activity.

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Salas-Lucia, F., Fekete, C., Sinko, R., Egri, P., Rada, K., Ruska, Y., Bocco, B., Fonseca, T. L., Gereben, B., Bianco, A. C.. 2022-08-18. A PATHWAY FOR T3 SIGNALING IN THE BRAIN TO IMPROVE THE VARIABLE EFFECTIVENESS OF THERAPY WITH L-T4. https://doi.org/10.1101/2022.08.17.504300

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