Filosofia

Solo disponible en BuenasTareas
  • Páginas : 35 (8738 palabras )
  • Descarga(s) : 0
  • Publicado : 23 de agosto de 2012
Leer documento completo
Vista previa del texto
insight review articles

Apoptosis in the nervous system
Junying Yuan* & Bruce A. Yankner†
*Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA (email: junying_yuan@hms.harvard.edu) †Department of Neurology, Harvard Medical School and Division of Neuroscience, Children’s Hospital, Enders 260, 300 Longwood Avenue, Boston, Massachusetts02115, USA (e-mail: yankner@a1.tch.harvard.edu)

Neuronal apoptosis sculpts the developing brain and has a potentially important role in neurodegenerative diseases. The principal molecular components of the apoptosis programme in neurons include Apaf-1 (apoptotic protease-activating factor 1) and proteins of the Bcl-2 and caspase families. Neurotrophins regulate neuronal apoptosis through the actionof critical protein kinase cascades, such as the phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase pathways. Similar cell-death-signalling pathways might be activated in neurodegenerative diseases by abnormal protein structures, such as amyloid fibrils in Alzheimer’s disease. Elucidation of the cell death machinery in neurons promises to provide multiple points of therapeuticintervention in neurodegenerative diseases.

lthough mature neurons are among the most long-lived cell types in mammals, immature neurons die in large numbers during development. Furthermore, neuronal cell death is the cardinal feature of both acute and chronic neurodegenerative diseases. How do neurons die? This is a difficult question and we have only recently begun to understand the basicmechanisms. Like all cells, neuronal survival requires trophic support. Viktor Hamburger and Rita Levi-Montalcini described in a seminal paper that the survival of developing neurons is directly related to the availability of their innervating targets1. This laid the foundation for the neurotrophin hypothesis2, which proposed that immature neurons compete for target-derived trophic factors that are inlimited supply; only those neurons that are successful in establishing correct synaptic connections would obtain trophic factor support to allow their survival. The neurotrophin hypothesis predicts correctly that neuronal survival requires a positive survival signal; it did not, however, provide a concrete hypothesis as to how neurons die in the absence of trophic support. It was assumed untilrecently that neurons die simply of passive starvation in the absence of trophic factors. In 1988, using cultured sympathetic neurons as a model system, Johnson and colleagues showed that inhibition of RNA and protein synthesis blocked sympathetic neuronal cell death induced by nerve growth factor (NGF) deprivation3, providing the first tangible evidence that neurons might actually instigate their owndemise. The identification of the programmed cell death genes ced-3, ced-4 and ced-9, in the nematode Caenorhabditis elegans and their mammalian homologues (see review in this issue by Meier et al., pages 796–801) opened a window of opportunity to examine the mechanism of neuronal cell death at the molecular level4. It was soon discovered that vertebrate neuronal cell death induced by trophicfactor deprivation requires the participation of cysteine proteases, later termed caspases, which are the mammalian homologues of the C. elegans cell death gene product CED-3 (ref. 5). This was the first functional evidence that trophic factor deprivation activates a cellular suicide programme in vertebrate neurons. What are the critical components of this neuronal suicide programme? How is itactivated by lack of trophic support during
802

A

development and by pathological conditions in neurodegenerative diseases? These questions have been studied intensively during the past decade and are the subject of this review.

Key molecules in neuronal apoptosis
Mammalian apoptosis is regulated by the Bcl-2 family of proteins, the adaptor protein Apaf-1 (for apoptotic protease-activating...
tracking img