The Role of Transthyretin in Oligodendrocyte Development

Abstract

Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs) in blood and cerebrospinal fluid. Previously, two reports identified TTR null mice as hypothyroid in the central nervous system (CNS). This prompted our investigations into developmentally regulated TH-dependent processes in brains of wildtype and TTR null mice. Despite logical expectations of a hypomyelinating phenotype in the CNS of TTR null mice, we observed a hypermyelination phenotype, synchronous with an increase in the density of oligodendrocytes in the corpus callosum and anterior commissure of TTR null mice during postnatal development. Furthermore, absence of TTR enhanced proliferation and migration of OPCs with decreased apoptosis. Neural stem cells (NSCs) isolated from the subventricular zone of TTR null mice at P21 revealed that the absence of TTR promoted NSC differentiation toward a glial lineage. Importantly, we identified TTR synthesis in OPCs, suggestive of an alternate biological function in these cells that may extend beyond an extracellular TH-distributor protein. The hypermyelination mechanism may involve increased pAKT (involved in oligodendrocyte maturation) in TTR null mice. Elucidating the regulatory role of TTR in NSC and OPC biology could lead to potential therapeutic strategies for the treatment of acquired demyelinating diseases.

Identification of key molecular biomarkers involved in reactive and neurodegenerative processes present in inherited congenital hydrocephalus

“…TTR is a protein with neuroprotective effects that is secreted into the cerebrospinal fluid (CSF) by the choroid plexus and the subcommissural organ [ 42 ]. Interestingly, OPCs use TTR for their differentiation [ 43 ]. For this reason, TTR was immunodetected in tissue sections, and the protein was found to be present in the choroid plexus of normal and hydrocephalic mice (Fig.…”

“…The overexpression of TTR in the white matter of hyh mice deserves attention because it could have a neuroprotective effect. Besides, TTR also promotes oligodendrocyte myelination from OPCs [ 43 , 67 ]. TTR is a distributor of thyroid hormones [ 67 ] that is mainly synthetized in the choroid plexus and released into CSF, where it is one of the more abundant proteins [ 68 ].…”

“…According to the absence of TTR found in different ventricle walls (see Additional file 4 ), a diffusion of TTR from the surfaces of the ventricles without ependyma appears to be improbable. However, the possibility of TTR diffusion in the oedematous white matter should not be discarded, where the OPCs could take the protein [ 43 ]. In any case, there is the possibility that TTR in the damaged white matter can be related to OPC function and oligodendrocyte development [ 43 ].…”

Thyroid Hormone and Neural Stem Cells: Repair Potential Following Brain and Spinal Cord Injury

“…Data on the regulation of TH metabolism in NSCs almost exclusively originates from rodent studies. MCT8 and OATP1C1 mediate TH uptake at the endothelial cells of the rodent BBB as they do in other brain regions ( Mayerl et al, 2014 ; Vatine et al, 2017 ), while TTR provides at least a part of T 4 to SVZ-NSCs via the CSF ( Vancamp et al, 2019 ; Alshehri et al, 2020 ). It is currently unknown which transporters facilitate TH uptake into SVZ-NSCs themselves.…”

“…These reduced TTR levels, together with the possibility that TTR protein sequesters amyloid β, could reduce T 4 availability ( Li and Buxbaum, 2011 ) and hamper TH supply to SVZ-NSCs, affecting SVZ-neuro- and oligodendrogenesis. Ttr KO mice had decreased numbers of newly SVZ-generated neuroblasts and favored glial fate choice ( Vancamp et al, 2019 ; Alshehri et al, 2020 ), reminiscent of the effects on SVZ-neurogliogenesis following hypothyroidism ( López-Juárez et al, 2012 ; Remaud et al, 2017 ).…”