Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.

https://science.sciencemag.org/content/sci/270/5240/1326.full.pdf

Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

The neurotrophins are a small group of dimeric proteins that profoundly affect the development of the nervous system of vertebrates. Recent studies have established clear correlations between the survival requirements for different neurotrophins of functionally distinct subsets of sensory neurons. The biological role of the neurotrophins is not limited to the prevention of programmed cell death of specific groups of neurons during development. Neurotrophin-3 in particular seems to act on neurons well before the period of target innervation and of normally occuning cell death. In animals lacking functional neurotrophin or receptor genes, neuronal numbers do not seem to be massively reduced in the CNS, unlike in the PNS. Finally, rapid actions of neurotrophins on synaptic efficacy, as well as the regulation of their mRNAs by electrical activity, suggest that neurotrophins might play important roles in regulating neuronal connectivity in the developing and in the adult central nervous system.

Physiology of the neurotrophins

https://www.liverpool.ac.uk/~dhedgar/BIOL456/2_signal%20transduction.pdf

Neurotrophin signal transduction in the nervous system.

Systemic lupus erythematosus is a multisystem autoimmune disease in which the autoantibody response targets a variety of autoantigens of diverse subcellular location. We show here that these autoantigens are clustered in two distinct populations of blebs at the surface of apoptotic cells. The population of smaller blebs contains fragmented endoplasmic reticulum (ER) and ribosomes, as well as the ribonucleoprotein, Ro. The larger blebs (apoptotic bodies) contain nucleosomal DNA, Ro, La, and the small nuclear ribonucleoproteins. These autoantigen clusters have in common their proximity to the ER and nuclear membranes, sites of increased generation of reactive oxygen species in apoptotic cells. Oxidative modification at these sites may be a mechanism that unites this diverse group of molecules together as autoantigens.

/pdf/autoantigens-targeted-in-systemic-lupus-erythematosus-are-3msgs8jv8e.pdf

Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.

Grasping objects: the cortical mechanisms of visuomotor transformation

Nerve growth factor (NGF) binding to cellular receptors is required for the survival of some neural cells. In contrast to TrkA, the high-affinity NGF receptor that transduces NGF signals for survival and differentiation, the function of the low-affinity NGF receptor, p75NGFR, remains uncertain. Expression of p75NGFR induced neural cell death constitutively when p75NGFR was unbound; binding by NGF or monoclonal antibody, however, inhibited cell death induced by p75NGFR. Thus, expression of p75NGFR may explain the dependence of some neural cells on NGF for survival. These findings also suggest that p75NGFR has some functional similarities to other members of a superfamily of receptors that include tumor necrosis factor receptors, Fas (Apo-1), and CD40.

http://science.sciencemag.org/content/sci/261/5119/345.full.pdf

Induction of Apoptosis by the Low-Affinity NGF Receptor

Neural-targeted gene therapy for rodent and primate hemiparkinsonism.

Temperature-sensitive immortalized neural cells may be utilized to produce genetically engineered neural transplants. We have used a similar approach with mdx myoblasts. Control and mdx myoblasts were immortalized with a recombinant retrovirus that effects the expression of a temperaturesensitive simian virus 40 large T antigen. The resultant cells divide indefinitely at 34°C, but differentiate at 38°C, both morphologically and immunocytochemically. Polymerase chain reaction analysis of RNA confirmed the presence of the dystrophin point mutation in the mdx cells and its absence in the control cells. A similar approach may be useful for the proliferation, modification, and reimplantation of autologous cells from patients with degenerative and dystrophic disorders such as Duchenne muscular dystrophy. © 1992 John Wiley & Sons, Inc.

Jie Yang

Papers

Induction of Apoptosis by the Low-Affinity NGF Receptor

Neural-targeted gene therapy for rodent and primate hemiparkinsonism.

Increasing the proliferative capacity of muscular dystrophy myoblasts.