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The Journal of Neuroscience, March 11, 2009, 29(10):3220-3232; doi:10.1523/JNEUROSCI.6012-08.2009

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Development/Plasticity/Repair
Transthyretin Internalization by Sensory Neurons Is Megalin Mediated and Necessary for Its Neuritogenic Activity

Carolina E. Fleming,^1,3 Fernando Milhazes Mar,¹ Filipa Franquinho,¹ Maria J. Saraiva,^1,2 and Mónica M. Sousa¹

¹Instituto de Biologia Molecular e Celular–IBMC, Nerve Regeneration Group and Molecular Neurobiology Group, 4150-180 Porto, Portugal, ²Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4099-003 Porto, Portugal, and ³Programa Doutoral em Biologia Experimental e Biomedicina, Universidade de Coimbra, 3004-517 Coimbra, Portugal

Correspondence should be addressed to Mónica M. Sousa, Nerve Regeneration Group, Instituto de Biologia Molecular e Celular–IBMC, R. Campo Alegre 823, 4150-180 Porto, Portugal. Email: msousa{at}ibmc.up.pt

Mutated transthyretin (TTR) causes familial amyloid polyneuropathy, a neurodegenerative disorder characterized by TTR deposition in the peripheral nervous system (PNS). The origin/reason for TTR deposition in the nerve is unknown. Here we demonstrate that both endogenous mouse TTR and TTR injected intravenously have access to the mouse sciatic nerve. We previously determined that in the absence of TTR, both neurite outgrowth in vitro and nerve regeneration in vivo were impaired. Reinforcing this finding, we now show that local TTR delivery to the crushed sciatic nerve rescues the regeneration phenotype of TTR knock-out (KO) mice. As the absence of TTR was unrelated to neuronal survival, we further evaluated the Schwann cell and inflammatory response to injury, as well as axonal retrograde transport, in the presence/absence of TTR. Only retrograde transport was impaired in TTR KO mice which, in addition to the neurite outgrowth impairment, might account for the decreased regeneration in this strain. Moreover, we show that in vitro, in dorsal root ganglia neurons, clathrin-dependent megalin-mediated TTR internalization is needed for TTR neuritogenic activity. Supporting this observation, we demonstrate that in vivo, decreased levels of megalin lead to decreased nerve regeneration and that megalin's action as a regeneration enhancer is dependent on TTR. In conclusion, our work unravels the mechanism of TTR action during nerve regeneration. Additionally, TTR presence in the nerve, as is here shown, may underlie its preferential deposition in the PNS of familial amyloid polyneuropathy patients.

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Received Dec. 18, 2008; revised Feb. 5, 2009; accepted Feb. 10, 2009.

Correspondence should be addressed to Mónica M. Sousa, Nerve Regeneration Group, Instituto de Biologia Molecular e Celular–IBMC, R. Campo Alegre 823, 4150-180 Porto, Portugal. Email: msousa{at}ibmc.up.pt

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