Axonal Self-Destruction and Neurodegeneration

Raff, Martin; Whitmore, Alan V.; Finn, John T.

doi:10.1126/science.1068613

Cited by 592 publications

(475 citation statements)

References 49 publications

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“…Likewise, in Parkinson's disease, modification of firing patterns of cortico-striatal pathways (Bézard et al, 2003) and loss of dopaminergic terminals (Herkenham et al, 1991) occur early in the asymptomatic phase of the disease. In fact, this synaptic dysfunction and damage has been recognised as an early event in the course of different other neurodegenerative diseases such as Huntington's (Li et al, 2001), prion's diseases (Ferrer, 2002), HIV infection (Garden et al, 2002), schizophrenia (Glantz et al, 2006), temporal lobe epilepsy (Ratté and Lacaille, 2006) or motor neuropathies (Raff et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Modification upon aging of the density of presynaptic modulation systems in the hippocampus

Canas

Duarte

Rodrigues

et al. 2009

Neurobiology of Aging

121

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Please cite this article in press as: Canas, P.M., et al., Modification upon aging of the density of presynaptic modulation systems in the hippocampus, Neurobiol Aging (2008) Abstract Different presynaptic neuromodulation systems have been explored as possible targets to manage neurodegenerative diseases. However, most studies used young adult animals whereas neurodegenerative diseases are prevalent in the elderly. Thus, we now explored by Western blot analysis how the density of different presynaptic markers and receptors changes with aging in rat hippocampal synaptosomes (purified nerve terminals). Compared to synaptosomal membranes from 2-month-old rats, the density of presynaptic proteins (synaptophysin or SNAP-25) decreased at 18-24 months. In parallel, markers of glutamatergic terminals (vGluT1 or vGluT2) and cholinergic terminal markers (vAChT) constantly decreased with aging from 12 to 18 months onwards, whereas the densities of GABAergic (vGAT) only decreased after 24 months. Inhibitory A 1 and CB 1 receptor density tended to decrease with aging, whereas facilitatory mGluR5 and P2Y1 receptor density was roughly constant and facilitatory A 2A receptor density increased at 18-24 months. Thus aging causes an imbalance of excitatory versus inhibitory nerve terminal markers and causes a predominant decrease of inhibitory rather than facilitatory presynaptic modulation systems.

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Section: Introductionmentioning

confidence: 99%

Modification upon aging of the density of presynaptic modulation systems in the hippocampus

Canas

Duarte

Rodrigues

et al. 2009

Neurobiology of Aging

121

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“…13,14 Disrupting the balance imposed by the BCL-2 family can lead to a host of human conditions that are characterized by excessive cellular demise, such as in neurodegenerative disease 15 or relentless cellular survival, such as in cancer 16 ( Figure 1). BCL-2 proteins are defined both by their structure 17 and function (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

BCL-2 in the crosshairs: tipping the balance of life and death

Walensky¹

2006

Cell Death Differ

225

175

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The discovery of B-cell lymphoma-2 (BCL-2) over 20 years ago revealed a new paradigm in cancer biology: the development and persistence of cancer can be driven by molecular roadblocks along the natural pathway to cell death. The subsequent identification of an expansive family of BCL-2 proteins provoked an intensive investigation of the interplay among these critical regulators of cell death. What emerged was a compelling tale of guardians and executioners, each participating in a molecular choreography that dictates cell fate. Ten years into the BCL-2 era, structural details defined how certain BCL-2 family proteins interact, and molecular targeting of the BCL-2 family has since become a pharmacological quest. Although many facets of BCL-2 family death signaling remain a mechanistic mystery, small molecules and peptides that effectively target BCL-2 are eliminating the roadblock to cell death, raising hopes for a medical breakthrough in cancer and other diseases of deregulated apoptosis.

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“…Axon degeneration is a common pathological event that is associated with different types of pathological conditions such as acute trauma, toxic insults and chronic neurodegenerative diseases (Raff et al, 2002;Coleman, 2005;Hilliard, 2008).…”

Section: Wld S As a Model To Study The Mechanisms Of Axon Degenerationmentioning

confidence: 99%

“…In vertebrates, the distal portion of a severed axon remains viable and conducts action potentials in vivo for up to a few days, after which they undergo a rapid structural destruction where the axolemma and axonal cytoskeleton are dismantled (Raff et al, 2002;Coleman, 2005;Luo and O'Leary, 2005). Morphologically, such a degenerative process is characterized by a beading appearance followed by granular disintegration of the axons.…”

Section: Wld S As a Model To Study The Mechanisms Of Axon Degenerationmentioning

confidence: 99%

“…It has become clear that many types of neurodegenerative diseases involve major synapse and axon losses before the appearance of symptoms, and even before the loss of neurons (Raff et al, 2002;Bjartmar et al, 2003;Saxena and Caroni, 2007). A variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, spinocerebellar disorders, peripheral neuropathies, nutritional neurological disorders, various intoxications and AIDS, are characterized by initial degeneration of the distal regions of long axons (Luo and O'Leary, 2005).…”

Section: Axon Degeneration Wld S and Neurodegenerative Diseasementioning

confidence: 99%

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WldS, Nmnats and axon degeneration-progress in the past two decades

Yan

et al. 2010

Protein Cell

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A chimeric protein called Wallerian degeneration slow (Wld S ) was first discovered in a spontaneous mutant strain of mice that exhibited delayed Wallerian degeneration. This provides a useful tool in elucidating the mechanisms of axon degeneration. Over-expression of Wld S attenuates the axon degeneration that is associated with several neurodegenerative disease models, suggesting a new logic for developing a potential protective strategy. At molecular level, although Wld S is a fusion protein, the nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) is required and sufficient for the protective effects of Wld S , indicating a critical role of NAD biosynthesis and perhaps energy metabolism in axon degeneration. These findings challenge the proposed model in which axon degeneration is operated by an active programmed process and thus may have important implication in understanding the mechanisms of neurodegeneration. In this review, we will summarize these recent findings and discuss their relevance to the mechanisms of axon degeneration.

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Axonal Self-Destruction and Neurodegeneration

Cited by 592 publications

References 49 publications

Modification upon aging of the density of presynaptic modulation systems in the hippocampus

Modification upon aging of the density of presynaptic modulation systems in the hippocampus

BCL-2 in the crosshairs: tipping the balance of life and death

WldS, Nmnats and axon degeneration-progress in the past two decades

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