ScienceWeek

NEUROSCIENCE: ON NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD)

The following points are made by A. Bedalov and J.A. Simon (Science 2004 305:954):

1) The cofactor nicotinamide adenine dinucleotide (NAD) -- once consigned to the oblivion of metabolic pathway wall charts -- has recently attained celebrity status as the link between metabolic activity, cellular resistance to stress or injury, and longevity. NAD influences many cell fate decisions -- for example, NAD-dependent enzymes such as poly (ADP-ribose) polymerase (PARP) are important for the DNA damage response, and NAD-dependent protein deacetylases (Sirtuins) are involved in transcriptional regulation, the stress response, and cellular differentiation. Araki et al (1) have extended the influence of NAD with a demonstration that an increase in NAD biosynthesis or enhanced activity of the NAD-dependent deacetylase SIRT1 protects mouse neurons from mechanical or chemical injury (2).

2) Axonal degeneration (termed Wallerian degeneration) often precedes the death of neuronal cell bodies in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Mice carrying the spontaneous dominant Wlds mutation show delayed axonal degeneration following neuronal injury. The Wlds mutation on mouse chromosome 4 is a rare tandem triplication of an 85-kb DNA fragment that harbors a translocation. The translocation encodes a fusion protein comprising the amino-terminal 70 amino acids of Ufd2a (ubiquitin fusion degradation protein 2a), an E4 ubiquitin ligase, and the entire coding region of Nmnat1 (nicotinamide mononucleotide adenylyltranferase 1), an NAD biosynthetic enzyme.

3) Although the C57BL/Wlds mouse was described 15 years ago (3) and expression of the Wlds fusion protein is known to delay Wallerian degeneration (4), the mechanism of neuroprotection has remained elusive. Given that proteasome inhibitors block Wallerian degeneration both in vitro and in vivo (5), the Ufd2a protein fragment (a component of the ubiquitin proteasome system) has been the prime candidate for mediator of neuroprotection in the Wlds mouse. Indeed, ubiquitin-mediated protein degradation by the proteasome has been identified as a potential target for developing drugs to treat neurodegenerative diseases such as AD, PD, and multiple sclerosis.

4) Araki et al (1) developed an in vitro model of Wallerian degeneration comprising cultures of primary dorsal root ganglion neurons derived from wild-type mice. The neurons overexpressed either the Wlds fusion protein or one of the fusion protein fragments. The authors found that overexpression of the Ufd2a protein fragment alone did not delay degeneration of axons injured by removal of the neuronal cell body (transection) or treatment with the neurotoxin vincristine. In contrast, overexpression of Nmnat1 or the addition of NAD to the neuronal cultures before injury delayed axonal degeneration in response to mechanical or chemical damage.

References (abridged):

1. T. Araki, Y. Sasaki, J. Milbrandt, Science 305, 1010 (2004)

2. A. Waller, Philos. Trans. R Soc. London 140, 423 (1850)

3. E. R. Lunn et al., Eur. J. Neurosci. 1, 27 (1989)

4. T. G. Mack et al., Nature Neurosci. 4, 1199 (2001)

5. Q. Zhai et al., Neuron, 39, 217 (2003)

Science http://www.sciencemag.org

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Related Material:

AXONAL SELF-DESTRUCTION AND NEURODEGENERATION

Science 2002 296:868

The following points are made by M.C. Raff et al:

1) Much effort is being devoted to understanding the nature of neuronal cell death in various neurodegenerative diseases such as motor neuron disease, glaucoma, and Alzheimer, Parkinson, and Huntington diseases (1-5). It may be, however, that neuronal death in these diseases occurs too late to be clinically important. Degeneration of the neuron's long process -- the axon -- often precedes the death of the cell body and may make a more important contribution to the patient's disability.

2) A classical example of axonal degeneration is "Wallerian degeneration", which occurs when an axon is cut. The part of the axon that is now disconnected from the cell body disassembles in a characteristic and orderly way. In vertebrates, this part of the axon can continue to conduct action potentials for a day or two when electrically stimulated, but it then quickly degenerates: The endoplasmic reticulum breaks down, the neurofilaments degrade, the mitochondria swell, and the axon breaks up into fragments that are phagocytosed. Wallerian degeneration can occur in both the peripheral nervous system (PNS) and central nervous system (CNS) whenever trauma, a vascular accident, infection, or an immune response locally injures axons.

3) From the perspective of neurodegenerative diseases, a more relevant form of axonal degeneration occurs in a process called "dying back". Here, the axon of an unhealthy neuron progressively degenerates over weeks or months, beginning distally and spreading toward the cell body. This is the most common pathology seen in peripheral nerve diseases caused by a wide variety of toxic, metabolic, and infectious insults. It occurs, for example, in the polyneuropathies associated with diabetes, alcoholism, acrylamide poisoning, and AIDS. It also seems to occur in CNS neurodegenerative diseases, including motor neuron disease and Alzheimer and Parkinson diseases, although it has been less well documented in these cases. The dying-back process is intriguing: How can a cell eliminate part of itself while leaving the rest intact? It contrasts with Wallerian degeneration, in which the axonal lesion itself both starts the destructive process and compartmentalizes it.

4) In summary: Neurons seem to have at least two self-destruct programs. Like other cell types, they have an intracellular death program for undergoing apoptosis when they are injured, infected, or not needed. In addition, they apparently have a second, molecularly distinct self-destruct program in their axon. This program is activated when the axon is severed and leads to the rapid degeneration of the isolated part of the cut axon. Do neurons also use this second program to prune their axonal tree during development and to conserve resources in response to chronic insults?

References (abridged):

1. C. Behl, J. Neural Transm. 107, 1325 (2000)

2. R. M. Gibson, Br. Med. J. 322, 1539 (2001)

3. N. Heintz and H. Y. Zoghbi, Annu. Rev. Physiol. 62, 779 (2000)

4. L. J. Martin, Int. J. Mol. Med. 7, 455 (2001)

5. N. N. Osborne, et al., Br. J. Ophthalmol. 83, 980 (1999)

Science http://www.sciencemag.org

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INHIBITING AXON DEGENERATION AND SYNAPSE LOSS ATTENUATES APOPTOSIS AND DISEASE PROGRESSION IN A MOUSE MODEL OF MOTONEURON DISEASE

Current Biology 2003 13:669

The following points are made by A. Ferri et al:

1) Apoptosis is a hallmark of motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) [1]. In a widely used mouse model of motoneuron disease (progressive motor neuronopathy or pmn) [2 4], transgenic expression of the anti-apoptotic bcl-2 gene [5] or treatment with glial cell-derived neurotrophic factor prevents the apoptosis of the motoneuron soma; however, these treatments were unable to affect the life span of the animals.

2) The authors report a study to determine whether the pmn phenotype could be rescued by means of a gene that inhibits axon degeneration. For this reason, the pmn mice were crossed with mice bearing the dominant Wlds ( slow Wallerian degeneration ) mutation, which slows axon degeneration and synapse. The authors demonstrate that the Wlds gene product attenuates symptoms, extends life span, prevents axon degeneration, rescues motoneuron number and size, and delays retrograde transport deficits in pmn/pmn mice. The authors suggest these results point to new pathogenic mechanisms and therapeutic avenues for motoneuron diseases.

References (abridged):

1. Cleveland, D. and Rothstein, J. (2001). From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat. Rev. Neurosci. 2, 806-819

2. Schmalbruch, H., Jensen, H.J., Bjaerg, M., Kamieniecka, Z., and Kurland, L. (1991). A new mouse model with progressive motor neuronopathy. J. Neuropathol. Exp. Neurol. 50, 192-204

3. Martin, N., Jaubert, J., Gounon, P., Salido, E., Haase, G., Szatanik, M., and Guenet, J.L. (2002). A missense mutation in Tbce causes progressive motor neuronopathy in mice. Nat. Genet. 32, 443-447

4. Bommel, H., Xie, G., Rossoll, W., Wiese, S., Jablonka, S., Boehm, T., and Sendtner, M. (2002). Missense mutation in the tubulin-specific chaperone E (Tbce) gene in the mouse mutant progressive motor neuronopathy, a model of human motoneuron disease. J. Cell Biol. 159, 563-569

5. Sagot, Y., Dubois-Dauphin, M., Tan, S.A., de Bilbao, F., Aebischer, P., Martinou, J.C., and Kato, A.C. (1995). Bcl-2 overexpression prevents motoneuron cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease. J. Neurosci. 15, 7727-7733

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