A Narrative Review of the Role of Transthyretin in Health and Disease
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REVIEW
A Narrative Review of the Role of Transthyretin in Health and Disease Marcia Almeida Liz . Teresa Coelho . Vittorio Bellotti . Maria Isabel Fernandez-Arias . Pablo Mallaina . Laura Obici
Received: August 19, 2020 / Accepted: September 23, 2020 Ó The Author(s) 2020
ABSTRACT Transthyretin (TTR) is a tetrameric transport protein highly conserved through vertebrate evolution and synthesized in the liver, choroid plexus, and retinal pigment epithelium. TTR transports the thyroid hormone thyroxine and the retinol-binding protein (RBP) bound to retinol (vitamin A). Mutations in TTR are associated with inherited transthyretin amyloidosis (ATTRv), a progressive, debilitating disease that is ultimately fatal and is characterized by
M. A. Liz Instituto de Investigac¸a˜o e Inovac¸a˜o em Sau´de (i3S), Universidade Do Porto, Porto, Portugal T. Coelho Centro Hospitalar Universita´rio Do Porto, Porto, Portugal V. Bellotti Wolfson Drug Discovery Unit, Division of Medicine, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK V. Bellotti Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Pavia, Italy M. I. Fernandez-Arias P. Mallaina Pfizer Global Medical Affairs, Madrid, Spain L. Obici (&) Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy e-mail: [email protected]
misfolding of TTR and aggregation as amyloid fibrils, predominantly leading to cardiomyopathy or polyneuropathy depending on the particular TTR mutation. Transthyretin amyloid cardiomyopathy can also occur as an age-related disease caused by misfolding of wild-type TTR. Apart from its transport role, little is known about possible additional physiological functions of TTR. Evidence from animal model systems in which TTR has been disrupted via gene knockout is adding to our cumulative understanding of TTR function. There is growing evidence that TTR may have a role in neuroprotection and promotion of neurite outgrowth in response to injury. Here, we review the literature describing potential roles of TTR in neurobiology and in the pathophysiology of diseases other than ATTR amyloidosis. A greater understanding of these processes may also contribute to further clarification of the pathology of ATTR and the effects of potential therapies for TTR-related conditions.
Keywords: Alzheimer’s disease; Amyloidosis; Neurodegeneration; Neuroprotection; Transthyretin
Neurol Ther
Key Summary Points Transthyretin is a highly conserved protein that transports the thyroid hormone thyroxine and the retinolbinding protein bound to retinol (vitamin A). Mutations in TTR are associated with ATTR amyloidosis, a progressive, debilitating, and ultimately fatal disease. ATTR amyloidosis can also occur as a spontaneous, age-related disease in individuals with non-mutated wild-type TTR. Aside from its function as a transport protein, there is a growing body of evidence for a role for TTR in neuroprotection and promotion of neurite outgrowth in response to injury. The
