1,720,991 research outputs found
Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons
No full textAlthough the mechanisms underlying the loss of neurons in Parkinson's disease are not well understood, impaired mitochondrial function and pathological protein aggregation are suspected as playing a major role. Why DA (dopamine) neurons and a select small subset of brain nuclei are particularly vulnerable to such ubiquitous cellular dysfunctions is presently one of the key unanswered questions in Parkinson's disease research. One intriguing hypothesis is that their heightened vulnerability is a consequence of their elevated bioenergetic requirements. Here, we show for the first time that vulnerable nigral DA neurons differ from less vulnerable DA neurons such as those of the VTA (ventral tegmental area) by having a higher basal rate of mitochondrial OXPHOS (oxidative phosphorylation), a smaller reserve capacity, a higher density of axonal mitochondria, an elevated level of basal oxidative stress, and a considerably more complex axonal arborization. Furthermore, we demonstrate that reducing axonal arborization by acting on axon guidance pathways with Semaphorin 7A reduces in parallel the basal rate of mitochondrial OXPHOS and the vulnerability of nigral DA neurons to the neurotoxic agents MPP(+) (1-methyl-4-phenylpyridinium) and rotenone. Blocking L-type calcium channels with isradipine was protective against MPP(+) but not rotenone. Our data provide the most direct demonstration to date in favor of the hypothesis that the heightened vulnerability of nigral DA neurons in Parkinson's disease is directly due to their particular bioenergetic and morphological characteristics
Caspace-3 deficiency rescues peripheral nervous system defect in pRb nullizygous mice.
No full textThe retinoblastoma tumour suppressor protein, pRb, is a key regulator of cell cycle and has been implicated in the terminal differentiation of neuronal cells. Mice nullizygous for pRb die by E14.5 from haematopoietic and neurological defects attributed to failed differentiation (Jacks et al., 1992; Lee et al., 1992; Clarke et al., 1992). Previous studies by Macleod et al., (1996) have demonstrated that the loss of p53 protects pRb-deficient central nervous system (CNS) neurons but not peripheral nervous system (PNS) neurons from cell death. Thus, the mechanisms by which PNS neurons undergo apoptosis in response to pRb deficiency remain unknown. In view of the pivotal role of caspase-3 in the regulation of neuronal apoptosis during development, we examined its function in the execution of the widespread neuronal cell death induced by pRb deficiency. Our results support a number of conclusions: First, we show that caspase-3 becomes activated in all neuronal populations undergoing apoptosis. Second, caspase-3 deficiency does not extend the life span of pRb null embryos, as double null mutants exhibit high rates of liver apoptosis resulting in erythropoietic failure. Third, pRb/caspase-3 double mutant neurons of the CNS exhibit widespread apoptosis similar to that seen in pRb mutants alone, thus caspase-3 deficiency does not protect this population from apoptosis. Finally, in contrast to the CNS, neurons of the PNS including those comprising the trigeminal ganglia (TG) and the dorsal root ganglia (DRG) are protected from apoptosis in pRb/caspase-3 double mutant embryos. Examination of the mechanistic differences between these two cell types revealed that CNS neurons invoke compensatory caspase activity that is not found in PNS neurons. These findings suggest that PNS neurons are dependent upon caspase-3 for the execution of apoptosis and that caspase-3 may serve as a key therapeutic target for neuroprotection following injury of this cell type
The Role of OPA1 and Interacting Proteins in Mitochondrial Function
No full textThe cell possesses a number of vital mechanisms to respond to different stressors. Mitochondria are dynamic organelles which undergo constant changes in length, transport and inner membrane structure and curvature. Invaginations of this inner membrane, cristae, have been known to respond to the energetic state of mitochondria, but the regulation of these changes as well as the consequences thereof remain undetermined. We find that Optic Atrophy 1 (OPA1), a protein involved in inner membrane fusion and cristae maintenance during cell death, can respond to the energetic state of mitochondria and the cell. Moreover, OPA1-dependent changes in cristae structure are required for resistance to starvation induced cell death, proper functioning of the electron transport chain, for growth in galactose media and for maintenance of ATP synthase assembly. Interestingly, we demonstrate that select members of the mitochondrial solute carriers (SLC25A) interact with OPA1 and affect the response of OPA1 to substrate levels. Taken together, we propose an SLC25A-dependent role for OPA1 in sensing energy substrate availability and responding to alter cristae, bioenergetics and cellular survival.
We also identified KIAA0664 as a novel OPA1-interacting protein, describe its subcellular localization and investigate its role in mitochondrial fusion and in mitochondrial localization. Finally, since both known carriers of mitochondrial glutathione were demonstrated to interact with OPA1, we investigated the role of OPA1 in cellular glutathione redox. OPA1 depleted cells demonstrated both increased total cellular glutathione and a shift in redox to its reduced form. The role of OPA1 in glutathione levels and redox ratios required GTPase activity, but surprisingly not fusion. Since glutathione is a master regulator of reactive oxygen species detoxification, these findings may shed light on the role of OPA1 in ROS-induced cell death pathways
The Role of OPA1 and Interacting Proteins in Mitochondrial Function
No full textThe cell possesses a number of vital mechanisms to respond to different stressors. Mitochondria are dynamic organelles which undergo constant changes in length, transport and inner membrane structure and curvature. Invaginations of this inner membrane, cristae, have been known to respond to the energetic state of mitochondria, but the regulation of these changes as well as the consequences thereof remain undetermined. We find that Optic Atrophy 1 (OPA1), a protein involved in inner membrane fusion and cristae maintenance during cell death, can respond to the energetic state of mitochondria and the cell. Moreover, OPA1-dependent changes in cristae structure are required for resistance to starvation induced cell death, proper functioning of the electron transport chain, for growth in galactose media and for maintenance of ATP synthase assembly. Interestingly, we demonstrate that select members of the mitochondrial solute carriers (SLC25A) interact with OPA1 and affect the response of OPA1 to substrate levels. Taken together, we propose an SLC25A-dependent role for OPA1 in sensing energy substrate availability and responding to alter cristae, bioenergetics and cellular survival.
We also identified KIAA0664 as a novel OPA1-interacting protein, describe its subcellular localization and investigate its role in mitochondrial fusion and in mitochondrial localization. Finally, since both known carriers of mitochondrial glutathione were demonstrated to interact with OPA1, we investigated the role of OPA1 in cellular glutathione redox. OPA1 depleted cells demonstrated both increased total cellular glutathione and a shift in redox to its reduced form. The role of OPA1 in glutathione levels and redox ratios required GTPase activity, but surprisingly not fusion. Since glutathione is a master regulator of reactive oxygen species detoxification, these findings may shed light on the role of OPA1 in ROS-induced cell death pathways
The Role of Pocket Proteins pRb and p107 in Radial Migration and Axon Guidance through Cell Cycle Independent Mechanisms
No full textPocket proteins (pRb, p107 and p130) are well studied in the role of regulating cell proliferation by controlling progression through the G1/S phase of the cell cycle. Increasing genetic and anatomical evidence suggests that these proteins also control early differentiation and even later stages of cell maturation including neural migration. However, the multifaceted functions of pocket proteins in the regulation of cell proliferation and cell death has complicated our interpretation of their role during development. As a result, the mechanisms through which pocket proteins regulate neuronal migration and neural maturation remain unknown. Using a pRb and p107 double knock out model, we show that a population of upper layer cortical neurons fails to pass through the intermediate zone into the cortical plate. Importantly, these neurons are born at the appropriate time and have exited the cell cycle. In addition, the role of pocket proteins in radial migration is independent cell death, since this migration defect cannot be rescued by eliminating ectopic cell death through Bax deletion. We also show a novel role of pRb and p107 in development of the dorsal midline and guidance of callosal axons. In the absence of pRb and p107, the structures of the commissural plate are highly disorganized and the callosal axons fail to cross the midline. We identify primary defects in axon extension and expression of multiple guidance cues, which can be observed prior to the disorganization of the midline axon guidance structures. Through the use of in vitro cortical explants and in utero electroporation, we identify defects in the rate of axon extension and directional guidance independent from the midline. In addition, protein levels of Netrin and Neuropilin-1 are decreased in the absence of pRb and p107, which could mediate the function of pocket proteins in guiding callosal axons. Indeed, we identify a previously undescribed population of Netrin expressing cells in the cingulate cortex of control embryos which is lost in the pRb/p107 deficient littermates. We propose that these cells play a significant role in callosal axon guidance during normal development. The results presented in this dissertation define multiple novel roles of pRb and p107 in the regulation of radial migration and axon guidance, independent from the role of these pocket proteins in cell death and proliferation
The Role of Pocket Proteins pRb and p107 in Radial Migration and Axon Guidance through Cell Cycle Independent Mechanisms
No full textPocket proteins (pRb, p107 and p130) are well studied in the role of regulating cell proliferation by controlling progression through the G1/S phase of the cell cycle. Increasing genetic and anatomical evidence suggests that these proteins also control early differentiation and even later stages of cell maturation including neural migration. However, the multifaceted functions of pocket proteins in the regulation of cell proliferation and cell death has complicated our interpretation of their role during development. As a result, the mechanisms through which pocket proteins regulate neuronal migration and neural maturation remain unknown. Using a pRb and p107 double knock out model, we show that a population of upper layer cortical neurons fails to pass through the intermediate zone into the cortical plate. Importantly, these neurons are born at the appropriate time and have exited the cell cycle. In addition, the role of pocket proteins in radial migration is independent cell death, since this migration defect cannot be rescued by eliminating ectopic cell death through Bax deletion. We also show a novel role of pRb and p107 in development of the dorsal midline and guidance of callosal axons. In the absence of pRb and p107, the structures of the commissural plate are highly disorganized and the callosal axons fail to cross the midline. We identify primary defects in axon extension and expression of multiple guidance cues, which can be observed prior to the disorganization of the midline axon guidance structures. Through the use of in vitro cortical explants and in utero electroporation, we identify defects in the rate of axon extension and directional guidance independent from the midline. In addition, protein levels of Netrin and Neuropilin-1 are decreased in the absence of pRb and p107, which could mediate the function of pocket proteins in guiding callosal axons. Indeed, we identify a previously undescribed population of Netrin expressing cells in the cingulate cortex of control embryos which is lost in the pRb/p107 deficient littermates. We propose that these cells play a significant role in callosal axon guidance during normal development. The results presented in this dissertation define multiple novel roles of pRb and p107 in the regulation of radial migration and axon guidance, independent from the role of these pocket proteins in cell death and proliferation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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