Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain

Abstract

The development of the brain, as well as mood and cognitive functions, are affected by thyroid hormone (TH) signaling. Neurons are the critical cellular target for TH action, with T3 regulating the expression of important neuronal gene sets. However, the steps involved in T3 signaling remain poorly known given that neurons express high levels of type 3 deiodinase (D3), which inactivates both T4 and T3. To investigate this mechanism, 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 T3 to the cell nucleus, and doubling the expression of a T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and D3, which transport and inactivate T3, respectively. Notwithstanding, T3 gets away from degradation because D3's active center is in the cytosol. Moreover, we used a unique mouse system to show that T3 implanted in specific brain areas can trigger selective signaling in distant locations, as far as the contralateral hemisphere. These findings provide a pathway for L-T3 to reach neurons and resolve the paradox of T3 signaling in the brain amid high D3 activity.

The Thr92Ala polymorphism in the type 2 deiodinase gene is linked to depression in patients with COVID-19 after hospital discharge

“…DIO2, essential for physiological function in the CNS, brown adipose tissue ( 25 ), and muscle ( 26 ), plays a pivotal role in local triiodothyronine (T3) production, influencing neurological development and function. Active T3 is produced within the brain by DIO2, predominantly by astrocytes, affecting genes associated with neuronal development, myelination, and synaptic transmission ( 27 , 28 ). Notably, studies on mice that lack DIO2 revealed reduced brain T3 content with mild neurological effects, such as altered emotional behaviors and memory processing.…”

Nongenomic roles of thyroid hormones and their derivatives in adult brain: are these compounds putative neurotransmitters?

“…The TH is carried by anterograde axonal transport from the locus coeruleus to terminal projection sites throughout the forebrain ( 33 ). Cultured neurons in a microfluidic chamber showed both anterograde and orthograde axonal transport of labeled T3 ( 34 ).…”

Impaired T3 uptake and action in MCT8-deficient cerebral organoids underlie Allan-Herndon-Dudley syndrome

“…Notwithstanding, the fact that MCT8 is widely expressed in the human brain ( 13 – 16 ) supports a broader role for MCT8 in T3 transport into neural cells. This seems to be the case in mouse neurons, where Mct8 is critical in an endosomal pathway that retrogradely transports T3 from distal axons to the cell nucleus of these cells ( 17 ). Another example is the neural progenitor cells of chicken embryos and adult mouse hippocampi, where Mct8 functions as a gatekeeper in the process of neurogenesis ( 18 , 19 ).…”