Browsing by Author "Martinez, Gabriela"

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    Collateral Sprouting of Peripheral Sensory Neurons Exhibits a Unique Transcriptomic Profile
    (2020) Lemaitre, Dominique; Llavero Hurtado, Maica; De Gregorio, Cristian; Onate, Maritza; Martinez, Gabriela; Catenaccio, Alejandra; Wishart, Thomas M.; Court, Felipe A.
    Peripheral nerve injuries result in motor and sensory dysfunction which can be recovered by compensatory or regenerative processes. In situations where axonal regeneration of injured neurons is hampered, compensation by collateral sprouting from uninjured neurons contributes to target reinnervation and functional recovery. Interestingly, this process of collateral sprouting from uninjured neurons has been associated with the activation of growth-associated programs triggered by Wallerian degeneration. Nevertheless, the molecular alterations at the transcriptomic level associated with these compensatory growth mechanisms remain to be fully elucidated. We generated a surgical model of partial sciatic nerve injury in mice to mechanistically study degeneration-induced collateral sprouting from spared fibers in the peripheral nervous system. Using next-generation sequencing and Ingenuity Pathway Analysis, we described the sprouting-associated transcriptome of uninjured sensory neurons and compare it with the activated by regenerating neurons. In vitro approaches were used to functionally assess sprouting gene candidates in the mechanisms of axonal growth. Using a novel animal model, we provide the first description of the sprouting transcriptome observed in uninjured sensory neurons after nerve injury. This collateral sprouting-associated transcriptome differs from that seen in regenerating neurons, suggesting a molecular program distinct from axonal growth. We further demonstrate that genetic upregulation of novel sprouting-associated genes activates a specific growth program in vitro, leading to increased neuronal branching. These results contribute to our understanding of the molecular mechanisms associated with collateral sprouting in vivo. The data provided here will therefore be instrumental in developing therapeutic strategies aimed at promoting functional recovery after injury to the nervous system.
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    Peroxisome Proliferator-activated Receptor γ Up-regulates the Bcl-2 Anti-apoptotic Protein in Neurons and Induces Mitochondrial Stabilization and Protection against Oxidative Stress and Apoptosis
    (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2007) Fuenzalida, Karen; Quintanilla, Rodrigo; Ramos, Patricio; Piderit, Daniela; Fuentealba, Rodrigo A.; Martinez, Gabriela; Inestrosa, Nibaldo C.; Bronfman, Miguel
    Peroxisome proliferator-activated receptor gamma(PPAR gamma) has been proposed as a therapeutic target for neurodegenerative diseases because of its anti-inflammatory action in glial cells. However, PPAR gamma agonists prevent beta-amyloid (A beta)-induced neurodegeneration in hippocampal neurons, and PPAR gamma is activated by the nerve growth factor (NGF) survival pathway, suggesting a neuroprotective anti-inflammatory independent action. Here we show that the PPAR gamma agonist rosiglitazone (RGZ) protects hippocampal and dorsal root ganglion neurons against A beta-induced mitochondrial damage and NGF deprivation-induced apoptosis, respectively, and promotes PC12 cell survival. In neurons and in PC12 cells RGZ protective effects are associated with increased expression of the Bcl-2 anti-apoptotic protein. NGF-differentiated PC12 neuronal cells constitutively overexpressing PPAR gamma are resistant to A beta-induced apoptosis and morphological changes and show functionally intact mitochondria and no increase in reactive oxygen species when challenged with up to 50 mu M H2O2. Conversely, cells expressing a dominant negative mutant of PPAR gamma show increased A beta-induced apoptosis and disruption of neuronal-like morphology and are highly sensitive to oxidative stress-induced impairment of mitochondrial function. Cells overexpressing PPAR gamma present a 4-to 5-fold increase in Bcl-2 protein content, whereas in dominant negative PPAR gamma-expressing cells, Bcl-2 is barely detected. Bcl-2 knockdown by small interfering RNA in cells overexpressing PPAR gamma results in increased sensitivity to A beta and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPAR gamma protective effects. PPAR gamma prosurvival action is independent of the signal-regulated MAPK or the Akt prosurvival pathways. Altogether, these data suggest that PPAR gamma supports survival in neurons in part through a mechanism involving increased expression of Bcl-2.