Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease

Marina Betancor,Óscar López-Pérez,Alicia Otero,Rosario Osta,Adelaida Hernaiz,Inmaculada Martín-Burriel,Tomás Barrio,Laura Moreno-Martínez,Rosa Bolea,Juan José Badiola

doi:10.1007/s12035-021-02489-5

Abstract

The non-toxic C-terminal fragment of the tetanus toxin (TTC) has been described as a neuroprotective molecule since it binds to Trk receptors and activates Trk-dependent signaling, activating neuronal survival pathways and inhibiting apoptosis. Previous in vivo studies have demonstrated the ability of this molecule to increase mice survival, inhibit apoptosis and regulate autophagy in murine models of neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of the cellular prion protein (PrPC) into an abnormal and misfolded isoform known as PrPSc. These diseases share different pathological features with other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson’s disease or Alzheimer’s disease. Hitherto, there are no effective therapies to treat prion diseases. Here, we present a pilot study to test the therapeutic potential of TTC to treat prion diseases. C57BL6 wild-type mice and the transgenic mice Tg338, which overexpress PrPC, were intracerebrally inoculated with scrapie prions and then subjected to a treatment consisting of repeated intramuscular injections of TTC. Our results indicate that TTC displays neuroprotective effects in the murine models of prion disease reducing apoptosis, regulating autophagy and therefore increasing neuronal survival, although TTC did not increase survival time in these models.

Highlights

Transmissible spongiform encephalopathies (TSEs), termed prion diseases, are fatal neurodegenerative disorders caused by prions that affect humans and a wide variety of animal species [1]
Molecular mechanisms involved in the pathogenesis of prion diseases are still unknown, several pathways have been proposed to play an important role in TSE-associated neurodegeneration, among which autophagy and apoptosis are relevant [4]
Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of PrPC into PrPSc, leading to the accumulation of PrPSc in the central nervous system and causing neuronal dysfunction and death resulting in spongiform degeneration

Summary

Introduction

Transmissible spongiform encephalopathies (TSEs), termed prion diseases, are fatal neurodegenerative disorders caused by prions that affect humans and a wide variety of animal species [1]. These diseases share, as the main pathogenic event, the conversion of the cellular prion protein (PrPC) into an abnormal and misfolded isoform known as PrPSc. These diseases share, as the main pathogenic event, the conversion of the cellular prion protein (PrPC) into an abnormal and misfolded isoform known as PrPSc This leads to the accumulation of P rPSc in the central nervous system (CNS), which causes neuronal dysfunction and cell death [2]. Molecular mechanisms involved in the pathogenesis of prion diseases are still unknown, several pathways have been proposed to play an important role in TSE-associated neurodegeneration, among which autophagy and apoptosis are relevant [4]

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