A Pathway for T3 Signaling in the Brain to Improve the Variable Effectiveness of Therapy With L-T4

Abstract

The effectiveness of therapy for hypothyroidism with levothyroxine (L-T4) depends on patient's 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.

T3 levels and thyroid hormone signaling

“…A common polymorphism in the DIO2 gene (Thr92Ala-DIO2), which alters the intracellular localization of the enzyme and reduces D2 activity by ~20%, has been associated with impaired effectiveness of LT4 in the treatment of hypothyroidism, and clinical improvement when liothyronine (LT3) was added to LT4 therapy (73,(86)(87)(88). Although not universally observed (89), these findings highlight the potential for the D2 pathway to affect normal TH signaling in the brain and modify the effectiveness of therapy with LT4.…”