Fernando Martinez Mar - Academia.edu (original) (raw)

Papers by Fernando Martinez Mar

Activating transcription factor 3 ATP Adenosine-5'-triphosphate BBB Blood-brain-barrier BDNF Brai... more Activating transcription factor 3 ATP Adenosine-5'-triphosphate BBB Blood-brain-barrier BDNF Brain-derived neurotrophic factor C3 C3-ADP-ribosyltransferase cAMP Cyclic adenosine monophosphate CE Cholesteryl esters Cer Ceramide cGMP Cyclic guanosine monophosphate CGN Cerebellar granule neurons CNS Central nervous system CO Cholesterol CREB cAMP response element-binding protein CRMP-2 Collapsin response mediator protein 2 Csk C-terminal Src kinase CSPG Chondroitin sulfate proteoglycans Abbreviation list 18 CST Corticospinal tract CTB Cholera toxin B clubs of the axons interrupted inside the white matter (central stumps). Two main varieties are presented: a. From a thick, terminal (retraction ball) or en passant varicosity arise several fine and pale radiations that get lost in the neighboring territories where they ramify and end in a pale tip. Because it evokes the shape of the tortoise, I named such a singular disposition the testudinoid apparatus. Although many advances have been made in the axonal regeneration field, and despite that several molecular mechanisms underlying axonal growth have been dissected, the general view has not changed greatly since the first descriptions by Ramon y Cajal. To date, despite of the several ongoing clinical trials, still only very limited axonal regeneration is achieved in the CNS. As such, new studies to understand and improve regeneration of CNS axons are of the utmost importance. along the radial glial process and leaves behind a trailing process that elongates tangentially in the intermediate zone (purple, 5). The cell body continues to migrate towards its final destination (the top of the cortical plate), while the axon rapidly elongates (6). The leading process gives rise to the apical dendrite (green, 7), which initiates local branching in the marginal zone (until radial A B blocks of the regrowing axons is obtained by local protein synthesis (Verma et al., 2005; Willis and Twiss, 2006; Gumy et al., 2010). Axonal mRNAs face great challenges: they need to be actively transported, stored and protected from degradation at their final destination. The RNA-binding proteins play an essential role in this process, by binding to cis-elements in the 5'-or 3'-untranslated regions (UTR). Upon RNA binding they control its transport, stability and translation (Bassell and Kelic, 2004; Patel et al., 2012). The best

Molecular Neurobiology, 2015

Following injury to peripheral axons, besides increased cyclic adenosine monophosphate (cAMP), th... more Following injury to peripheral axons, besides increased cyclic adenosine monophosphate (cAMP), the positive injury signals extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT-3) are locally activated and retrogradely transported to the cell body, where they induce a pro-regenerative program. Here, to further understand the importance of injury signaling for successful axon regeneration, we used dorsal root ganglia (DRG) neurons that have a central branch without regenerative capacity and a peripheral branch that regrows after lesion. Although injury to the DRG central branch (dorsal root injury (DRI)) activated ERK, JNK, and STAT-3 and increased cAMP levels, it did not elicit gain of intrinsic growth capacity nor the ability to overcome myelin inhibition, as occurred after peripheral branch injury (sciatic nerve injury (SNI)). Besides, gain of growth capacity after SNI was independent of ERK and cAMP. Antibody microarrays of dynein-immunoprecipitated axoplasm from rats with either DRI or SNI revealed a broad differential activation and transport of signals after each injury type and further supported that ERK, JNK, STAT-3, and cAMP signaling pathways are minor contributors to the differential intrinsic axon growth capacity of both injury models. Increased levels of inhibitory injury signals including GSK3β and ROCKII were identified after DRI, not only in axons but also in DRG cell bodies. In summary, our work shows that activation and transport of positive injury signals are not sufficient to promote increased axon growth capacity and that differential modulation of inhibitory molecules may contribute to limited regenerative response.

BMC Biol, 2014

Background: In the adult central nervous system, axonal regeneration is abortive. Regulators of m... more Background: In the adult central nervous system, axonal regeneration is abortive. Regulators of microtubule dynamics have emerged as attractive targets to promote axonal growth following injury as microtubule organization is pivotal for growth cone formation. In this study, we used conditioned neurons with high regenerative capacity to further dissect cytoskeletal mechanisms that might be involved in the gain of intrinsic axon growth capacity. Results: Following a phospho-site broad signaling pathway screen, we found that in conditioned neurons with high regenerative capacity, decreased glycogen synthase kinase 3β (GSK3β) activity and increased microtubule growth speed in the growth cone were present. To investigate the importance of GSK3β regulation during axonal regeneration in vivo, we used three genetic mouse models with high, intermediate or no GSK3β activity in neurons. Following spinal cord injury, reduced GSK3β levels or complete neuronal deletion of GSK3β led to increased growth cone microtubule growth speed and promoted axon regeneration. While several microtubule-interacting proteins are GSK3β substrates, phospho-mimetic collapsin response mediator protein 2 (T/D-CRMP-2) was sufficient to decrease microtubule growth speed and neurite outgrowth of conditioned neurons and of GSK3β-depleted neurons, prevailing over the effect of decreased levels of phosphorylated microtubule-associated protein 1B (MAP1B) and through a mechanism unrelated to decreased levels of phosphorylated cytoplasmic linker associated protein 2 (CLASP2). In addition, phospho-resistant T/A-CRMP-2 counteracted the inhibitory myelin effect on neurite growth, further supporting the GSK3β-CRMP-2 relevance during axon regeneration. Conclusions: Our work shows that increased microtubule growth speed in the growth cone is present in conditions of increased axonal growth, and is achieved following inactivation of the GSK3β-CRMP-2 pathway, enhancing axon regeneration through the glial scar. In this context, our results support that a precise control of microtubule dynamics, specifically in the growth cone, is required to optimize axon regrowth.

International Review of Neurobiology, 2009

Transthyretin (TTR), a plasma and cerebrospinal fluid protein secreted by the liver and choroid p... more Transthyretin (TTR), a plasma and cerebrospinal fluid protein secreted by the liver and choroid plexus, is mainly known as the physiological carrier of thyroxine (T(4)) and retinol. Under pathological conditions, various TTR mutations are related to familial amyloid polyneuropathy (FAP), a neurodegenerative disorder characterized by deposition of TTR amyloid fibrils, particularly in the peripheral nervous system (PNS), leading to axonal loss and neuronal death. Recently, a number of TTR functions in neurobiology have been described; these may explain the preferential TTR deposition, when mutated, in the PNS of FAP patients. In this respect, and with a particular relevance in the PNS, TTR has been shown to have the ability to enhance neurite outgrowth in vitro and nerve regeneration following injury, in vivo. In the following pages, this novel TTR function, as well as its importance in nerve biology and repair will be discussed.

Molecular Neurobiology, 2015

Lack of axon regeneration following spinal cord injury has been mainly ascribed to the inhibitory... more Lack of axon regeneration following spinal cord injury has been mainly ascribed to the inhibitory environment of the injury site, i.e., to chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs). Here, we used shiverer (shi) mice to assess axon regeneration following spinal cord injury in the presence of MAIs and CSPG but in the absence of compact myelin. Although in vitro shi neurons displayed a similar intrinsic neurite outgrowth to wild-type neurons, in vivo, shi fibers had increased regenerative capacity, suggesting that the wild-type spinal cord contains additional inhibitors besides MAIs and CSPG. Our data show that besides myelin protein, myelin lipids are highly inhibitory for neurite outgrowth and suggest that this inhibitory effect is released in the shi spinal cord given its decreased lipid content. Specifically, we identified cholesterol and sphingomyelin as novel myelin-associated inhibitors that operate through a Rhodependent mechanism and have inhibitory activity in multiple neuron types. We further demonstrated the inhibitory action of myelin lipids in vivo, by showing that delivery of 2hydroxypropyl-β-cyclodextrin, a drug that reduces the levels of lipids specifically in the injury site, leads to increased axon regeneration of wild-type (WT) dorsal column axons following spinal cord injury. In summary, our work shows that myelin lipids are important modulators of axon regeneration that should be considered together with protein MAIs as critical targets in strategies aiming at improving axonal growth following injury. Keywords Axon regeneration. Spinal cord injury. Shiverer mice. Myelin lipid. Cholesterol. Sphingomyelin myelin-associated inhibitors (MAIs), namely Nogo, myelinassociated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) [3]; canonical axon guidance molecules, such as semaphorin 3A, ephrin B3, netrin-1, and repulsive guidance molecule A (RGMa) [4]; and chondroitin sulfate proteoglycans (CSPGs), produced by astrocytes [5]. Studies from different groups using triple knockout mice for MAG, Nogo, and OMgp produced conflicting results ranging from limited [6] to extensive [7] regeneration abilities. Although the field has largely concentrated on MAIs, other Mónica M. Sousa and Pedro Brites contributed equally to this work.

The Journal of Neuroscience, 2009

Mutated transthyretin (TTR) causes familial amyloid polyneuropathy, a neurodegenerative disorder ... more 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 outgrowthin vitroand nerve regenerationin vivowere 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 ...

The Journal of Neuroscience, 2014

Despite the inability of CNS axons to regenerate, an increased regenerative capacity can be elici... more Despite the inability of CNS axons to regenerate, an increased regenerative capacity can be elicited following conditioning lesion to the peripheral branch of dorsal root ganglia neurons (DRGs). Byin vivoradiolabeling of rat DRGs, coupled to mass spectrometry and kinesin immunoprecipitation of spinal cord extracts, we determined that the anterograde transport of cytoskeleton components, metabolic enzymes and axonal regeneration enhancers, was increased in the central branch of DRGs following a peripheral conditioning lesion. Axonal transport of mitochondria was also increased in the central branch ofThy1-MitoCFPmice following a peripheral injury. This effect was generalized and included augmented transport of lysosomes and synaptophysin- and APP-carrying vesicles. Changes in axonal transport were only elicited by a peripheral lesion and not by spinal cord injury. In mice, elevated levels of motors and of polyglutamylated and tyrosinated tubulin were present following a peripheral le...

Journal of Cellular and Molecular Medicine, 2012

Spinal cord injury triggers a complex set of events that lead to tissue healing without the resto... more Spinal cord injury triggers a complex set of events that lead to tissue healing without the restoration of normal function due to the poor regenerative capacity of the spinal cord. Nevertheless, current knowledge about the intrinsic regenerative ability of central nervous system axons, when in a supportive environment, has made the prospect of treating spinal cord injury a reality. Among the range of strategies under investigation, cell-based therapies offer the most promising results, due to the multifactorial roles that these cells can fulfil. However, the best cell source is still a matter of debate, as are clinical issues that include the optimal cell dose as well as the timing and route of administration. In this context, the role of biomaterials is gaining importance. These can not only act as vehicles for the administered cells but also, in the case of chronic lesions, can be used to fill the permanent cyst, thus creating a more favourable and conducive environment for axonal regeneration in addition to serving as local delivery systems of therapeutic agents to improve the regenerative milieu. Some of the candidate molecules for the future are discussed in view of the knowledge derived from studying the mechanisms that facilitate the intrinsic regenerative capacity of central nervous system neurons. The future challenge for the multidisciplinary teams working in the field is to translate the knowledge acquired in basic research into effective combinatorial therapies to be applied in the clinic.

IUBMB Life, 2010

Transthyretin (TTR) is a plasma and cerebrospinal fluid protein mainly recognized as the transpor... more Transthyretin (TTR) is a plasma and cerebrospinal fluid protein mainly recognized as the transporter of thyroxine (T(4)) and retinol. Mutated TTR leads to familial amyloid polyneuropathy, a neurodegenerative disorder characterized by TTR amyloid deposition particularly in peripheral nerves. Beside its transport activities, TTR is a cryptic protease and participates in the biology of the nervous system. Several studies have been directed at finding new ligands of TTR to further explore the biology of the protein. From the identified ligands, some were in fact TTR protease substrates. In this review, we will discuss the existent information concerning TTR ligands/substrates.

Future Neurology, 2009

Transthyretin (TTR) is the protein transporter of thyroxine and retinol. Several TTR mutations ar... more Transthyretin (TTR) is the protein transporter of thyroxine and retinol. Several TTR mutations are associated with familial amyloid polyneuropathy, a neurodegenerative disorder characterized by extracellular deposition of TTR aggregates and fibrils in the peripheral nervous system. Several reports suggest new TTR functions in the nervous system particularly in nerve regeneration and in neuroprotection in Alzheimer’s disease. The fact that TTR increases axonal growth during peripheral nervous system, regeneration and allows an appropriate retrograde transport may represent the missing link explaining the preferential deposition of mutated TTR in the peripheral nervous system of familial amyloid polyneuropathy patients. This paper discusses the details explaining the role of TTR during nerve regeneration.

EMBO reports, 2014

Although neurons execute a cell intrinsic program of axonal growth during development, following ... more Although neurons execute a cell intrinsic program of axonal growth during development, following the establishment of connections, the developmental growth capacity declines. Besides environmental challenges, this switch largely accounts for the failure of adult central nervous system (CNS) axons to regenerate. Here, we discuss the cell intrinsic control of axon regeneration, including not only the regulation of transcriptional and epigenetic mechanisms, but also the modulation of local protein translation, retrograde and anterograde axonal transport, and microtubule dynamics. We further explore the causes underlying the failure of CNS neurons to mount a vigorous regenerative response, and the paradigms demonstrating the activation of cell intrinsic axon growth programs. Finally, we present potential mechanisms to support axon regeneration, as these may represent future therapeutic approaches to promote recovery following CNS injury and disease.

Biochemical Journal, 2009

Besides functioning as the plasma transporter of retinol and thyroxine, TTR (transthyretin) is a ... more Besides functioning as the plasma transporter of retinol and thyroxine, TTR (transthyretin) is a protease, cleaving apoA-I (apolipoprotein A-I) after a phenylalanine residue. In the present study, we further investigated TTR substrate specificity. By using both P-diverse libraries and a library of phosphonate inhibitors, a TTR preference for a lysine residue in P1 was determined, suggesting that TTR might have a dual specificity and that, in addition to apoA-I, other TTR substrates might exist. Previous studies revealed that TTR is involved in the homoeostasis of the nervous system, as it participates in neuropeptide maturation and enhances nerve regeneration. We investigated whether TTR proteolytic activity is involved in these functions. Both wild-type TTR and TTRprot− (proteolytically inactive TTR) had a similar effect in the expression of peptidylglycine α-amidating mono-oxygenase, the rate-limiting enzyme in neuropeptide amidation, excluding the involvement of TTR proteolytic a...

Activating transcription factor 3 ATP Adenosine-5'-triphosphate BBB Blood-brain-barrier BDNF Brai... more Activating transcription factor 3 ATP Adenosine-5'-triphosphate BBB Blood-brain-barrier BDNF Brain-derived neurotrophic factor C3 C3-ADP-ribosyltransferase cAMP Cyclic adenosine monophosphate CE Cholesteryl esters Cer Ceramide cGMP Cyclic guanosine monophosphate CGN Cerebellar granule neurons CNS Central nervous system CO Cholesterol CREB cAMP response element-binding protein CRMP-2 Collapsin response mediator protein 2 Csk C-terminal Src kinase CSPG Chondroitin sulfate proteoglycans Abbreviation list 18 CST Corticospinal tract CTB Cholera toxin B clubs of the axons interrupted inside the white matter (central stumps). Two main varieties are presented: a. From a thick, terminal (retraction ball) or en passant varicosity arise several fine and pale radiations that get lost in the neighboring territories where they ramify and end in a pale tip. Because it evokes the shape of the tortoise, I named such a singular disposition the testudinoid apparatus. Although many advances have been made in the axonal regeneration field, and despite that several molecular mechanisms underlying axonal growth have been dissected, the general view has not changed greatly since the first descriptions by Ramon y Cajal. To date, despite of the several ongoing clinical trials, still only very limited axonal regeneration is achieved in the CNS. As such, new studies to understand and improve regeneration of CNS axons are of the utmost importance. along the radial glial process and leaves behind a trailing process that elongates tangentially in the intermediate zone (purple, 5). The cell body continues to migrate towards its final destination (the top of the cortical plate), while the axon rapidly elongates (6). The leading process gives rise to the apical dendrite (green, 7), which initiates local branching in the marginal zone (until radial A B blocks of the regrowing axons is obtained by local protein synthesis (Verma et al., 2005; Willis and Twiss, 2006; Gumy et al., 2010). Axonal mRNAs face great challenges: they need to be actively transported, stored and protected from degradation at their final destination. The RNA-binding proteins play an essential role in this process, by binding to cis-elements in the 5'-or 3'-untranslated regions (UTR). Upon RNA binding they control its transport, stability and translation (Bassell and Kelic, 2004; Patel et al., 2012). The best

Molecular Neurobiology, 2015

Following injury to peripheral axons, besides increased cyclic adenosine monophosphate (cAMP), th... more Following injury to peripheral axons, besides increased cyclic adenosine monophosphate (cAMP), the positive injury signals extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT-3) are locally activated and retrogradely transported to the cell body, where they induce a pro-regenerative program. Here, to further understand the importance of injury signaling for successful axon regeneration, we used dorsal root ganglia (DRG) neurons that have a central branch without regenerative capacity and a peripheral branch that regrows after lesion. Although injury to the DRG central branch (dorsal root injury (DRI)) activated ERK, JNK, and STAT-3 and increased cAMP levels, it did not elicit gain of intrinsic growth capacity nor the ability to overcome myelin inhibition, as occurred after peripheral branch injury (sciatic nerve injury (SNI)). Besides, gain of growth capacity after SNI was independent of ERK and cAMP. Antibody microarrays of dynein-immunoprecipitated axoplasm from rats with either DRI or SNI revealed a broad differential activation and transport of signals after each injury type and further supported that ERK, JNK, STAT-3, and cAMP signaling pathways are minor contributors to the differential intrinsic axon growth capacity of both injury models. Increased levels of inhibitory injury signals including GSK3β and ROCKII were identified after DRI, not only in axons but also in DRG cell bodies. In summary, our work shows that activation and transport of positive injury signals are not sufficient to promote increased axon growth capacity and that differential modulation of inhibitory molecules may contribute to limited regenerative response.

BMC Biol, 2014

Background: In the adult central nervous system, axonal regeneration is abortive. Regulators of m... more Background: In the adult central nervous system, axonal regeneration is abortive. Regulators of microtubule dynamics have emerged as attractive targets to promote axonal growth following injury as microtubule organization is pivotal for growth cone formation. In this study, we used conditioned neurons with high regenerative capacity to further dissect cytoskeletal mechanisms that might be involved in the gain of intrinsic axon growth capacity. Results: Following a phospho-site broad signaling pathway screen, we found that in conditioned neurons with high regenerative capacity, decreased glycogen synthase kinase 3β (GSK3β) activity and increased microtubule growth speed in the growth cone were present. To investigate the importance of GSK3β regulation during axonal regeneration in vivo, we used three genetic mouse models with high, intermediate or no GSK3β activity in neurons. Following spinal cord injury, reduced GSK3β levels or complete neuronal deletion of GSK3β led to increased growth cone microtubule growth speed and promoted axon regeneration. While several microtubule-interacting proteins are GSK3β substrates, phospho-mimetic collapsin response mediator protein 2 (T/D-CRMP-2) was sufficient to decrease microtubule growth speed and neurite outgrowth of conditioned neurons and of GSK3β-depleted neurons, prevailing over the effect of decreased levels of phosphorylated microtubule-associated protein 1B (MAP1B) and through a mechanism unrelated to decreased levels of phosphorylated cytoplasmic linker associated protein 2 (CLASP2). In addition, phospho-resistant T/A-CRMP-2 counteracted the inhibitory myelin effect on neurite growth, further supporting the GSK3β-CRMP-2 relevance during axon regeneration. Conclusions: Our work shows that increased microtubule growth speed in the growth cone is present in conditions of increased axonal growth, and is achieved following inactivation of the GSK3β-CRMP-2 pathway, enhancing axon regeneration through the glial scar. In this context, our results support that a precise control of microtubule dynamics, specifically in the growth cone, is required to optimize axon regrowth.

International Review of Neurobiology, 2009

Transthyretin (TTR), a plasma and cerebrospinal fluid protein secreted by the liver and choroid p... more Transthyretin (TTR), a plasma and cerebrospinal fluid protein secreted by the liver and choroid plexus, is mainly known as the physiological carrier of thyroxine (T(4)) and retinol. Under pathological conditions, various TTR mutations are related to familial amyloid polyneuropathy (FAP), a neurodegenerative disorder characterized by deposition of TTR amyloid fibrils, particularly in the peripheral nervous system (PNS), leading to axonal loss and neuronal death. Recently, a number of TTR functions in neurobiology have been described; these may explain the preferential TTR deposition, when mutated, in the PNS of FAP patients. In this respect, and with a particular relevance in the PNS, TTR has been shown to have the ability to enhance neurite outgrowth in vitro and nerve regeneration following injury, in vivo. In the following pages, this novel TTR function, as well as its importance in nerve biology and repair will be discussed.

Molecular Neurobiology, 2015

Lack of axon regeneration following spinal cord injury has been mainly ascribed to the inhibitory... more Lack of axon regeneration following spinal cord injury has been mainly ascribed to the inhibitory environment of the injury site, i.e., to chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs). Here, we used shiverer (shi) mice to assess axon regeneration following spinal cord injury in the presence of MAIs and CSPG but in the absence of compact myelin. Although in vitro shi neurons displayed a similar intrinsic neurite outgrowth to wild-type neurons, in vivo, shi fibers had increased regenerative capacity, suggesting that the wild-type spinal cord contains additional inhibitors besides MAIs and CSPG. Our data show that besides myelin protein, myelin lipids are highly inhibitory for neurite outgrowth and suggest that this inhibitory effect is released in the shi spinal cord given its decreased lipid content. Specifically, we identified cholesterol and sphingomyelin as novel myelin-associated inhibitors that operate through a Rhodependent mechanism and have inhibitory activity in multiple neuron types. We further demonstrated the inhibitory action of myelin lipids in vivo, by showing that delivery of 2hydroxypropyl-β-cyclodextrin, a drug that reduces the levels of lipids specifically in the injury site, leads to increased axon regeneration of wild-type (WT) dorsal column axons following spinal cord injury. In summary, our work shows that myelin lipids are important modulators of axon regeneration that should be considered together with protein MAIs as critical targets in strategies aiming at improving axonal growth following injury. Keywords Axon regeneration. Spinal cord injury. Shiverer mice. Myelin lipid. Cholesterol. Sphingomyelin myelin-associated inhibitors (MAIs), namely Nogo, myelinassociated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) [3]; canonical axon guidance molecules, such as semaphorin 3A, ephrin B3, netrin-1, and repulsive guidance molecule A (RGMa) [4]; and chondroitin sulfate proteoglycans (CSPGs), produced by astrocytes [5]. Studies from different groups using triple knockout mice for MAG, Nogo, and OMgp produced conflicting results ranging from limited [6] to extensive [7] regeneration abilities. Although the field has largely concentrated on MAIs, other Mónica M. Sousa and Pedro Brites contributed equally to this work.

The Journal of Neuroscience, 2009

Mutated transthyretin (TTR) causes familial amyloid polyneuropathy, a neurodegenerative disorder ... more 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 outgrowthin vitroand nerve regenerationin vivowere 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 ...

The Journal of Neuroscience, 2014

Despite the inability of CNS axons to regenerate, an increased regenerative capacity can be elici... more Despite the inability of CNS axons to regenerate, an increased regenerative capacity can be elicited following conditioning lesion to the peripheral branch of dorsal root ganglia neurons (DRGs). Byin vivoradiolabeling of rat DRGs, coupled to mass spectrometry and kinesin immunoprecipitation of spinal cord extracts, we determined that the anterograde transport of cytoskeleton components, metabolic enzymes and axonal regeneration enhancers, was increased in the central branch of DRGs following a peripheral conditioning lesion. Axonal transport of mitochondria was also increased in the central branch ofThy1-MitoCFPmice following a peripheral injury. This effect was generalized and included augmented transport of lysosomes and synaptophysin- and APP-carrying vesicles. Changes in axonal transport were only elicited by a peripheral lesion and not by spinal cord injury. In mice, elevated levels of motors and of polyglutamylated and tyrosinated tubulin were present following a peripheral le...

Journal of Cellular and Molecular Medicine, 2012

Spinal cord injury triggers a complex set of events that lead to tissue healing without the resto... more Spinal cord injury triggers a complex set of events that lead to tissue healing without the restoration of normal function due to the poor regenerative capacity of the spinal cord. Nevertheless, current knowledge about the intrinsic regenerative ability of central nervous system axons, when in a supportive environment, has made the prospect of treating spinal cord injury a reality. Among the range of strategies under investigation, cell-based therapies offer the most promising results, due to the multifactorial roles that these cells can fulfil. However, the best cell source is still a matter of debate, as are clinical issues that include the optimal cell dose as well as the timing and route of administration. In this context, the role of biomaterials is gaining importance. These can not only act as vehicles for the administered cells but also, in the case of chronic lesions, can be used to fill the permanent cyst, thus creating a more favourable and conducive environment for axonal regeneration in addition to serving as local delivery systems of therapeutic agents to improve the regenerative milieu. Some of the candidate molecules for the future are discussed in view of the knowledge derived from studying the mechanisms that facilitate the intrinsic regenerative capacity of central nervous system neurons. The future challenge for the multidisciplinary teams working in the field is to translate the knowledge acquired in basic research into effective combinatorial therapies to be applied in the clinic.

IUBMB Life, 2010

Transthyretin (TTR) is a plasma and cerebrospinal fluid protein mainly recognized as the transpor... more Transthyretin (TTR) is a plasma and cerebrospinal fluid protein mainly recognized as the transporter of thyroxine (T(4)) and retinol. Mutated TTR leads to familial amyloid polyneuropathy, a neurodegenerative disorder characterized by TTR amyloid deposition particularly in peripheral nerves. Beside its transport activities, TTR is a cryptic protease and participates in the biology of the nervous system. Several studies have been directed at finding new ligands of TTR to further explore the biology of the protein. From the identified ligands, some were in fact TTR protease substrates. In this review, we will discuss the existent information concerning TTR ligands/substrates.

Future Neurology, 2009

Transthyretin (TTR) is the protein transporter of thyroxine and retinol. Several TTR mutations ar... more Transthyretin (TTR) is the protein transporter of thyroxine and retinol. Several TTR mutations are associated with familial amyloid polyneuropathy, a neurodegenerative disorder characterized by extracellular deposition of TTR aggregates and fibrils in the peripheral nervous system. Several reports suggest new TTR functions in the nervous system particularly in nerve regeneration and in neuroprotection in Alzheimer’s disease. The fact that TTR increases axonal growth during peripheral nervous system, regeneration and allows an appropriate retrograde transport may represent the missing link explaining the preferential deposition of mutated TTR in the peripheral nervous system of familial amyloid polyneuropathy patients. This paper discusses the details explaining the role of TTR during nerve regeneration.

EMBO reports, 2014

Although neurons execute a cell intrinsic program of axonal growth during development, following ... more Although neurons execute a cell intrinsic program of axonal growth during development, following the establishment of connections, the developmental growth capacity declines. Besides environmental challenges, this switch largely accounts for the failure of adult central nervous system (CNS) axons to regenerate. Here, we discuss the cell intrinsic control of axon regeneration, including not only the regulation of transcriptional and epigenetic mechanisms, but also the modulation of local protein translation, retrograde and anterograde axonal transport, and microtubule dynamics. We further explore the causes underlying the failure of CNS neurons to mount a vigorous regenerative response, and the paradigms demonstrating the activation of cell intrinsic axon growth programs. Finally, we present potential mechanisms to support axon regeneration, as these may represent future therapeutic approaches to promote recovery following CNS injury and disease.

Biochemical Journal, 2009

Besides functioning as the plasma transporter of retinol and thyroxine, TTR (transthyretin) is a ... more Besides functioning as the plasma transporter of retinol and thyroxine, TTR (transthyretin) is a protease, cleaving apoA-I (apolipoprotein A-I) after a phenylalanine residue. In the present study, we further investigated TTR substrate specificity. By using both P-diverse libraries and a library of phosphonate inhibitors, a TTR preference for a lysine residue in P1 was determined, suggesting that TTR might have a dual specificity and that, in addition to apoA-I, other TTR substrates might exist. Previous studies revealed that TTR is involved in the homoeostasis of the nervous system, as it participates in neuropeptide maturation and enhances nerve regeneration. We investigated whether TTR proteolytic activity is involved in these functions. Both wild-type TTR and TTRprot− (proteolytically inactive TTR) had a similar effect in the expression of peptidylglycine α-amidating mono-oxygenase, the rate-limiting enzyme in neuropeptide amidation, excluding the involvement of TTR proteolytic a...