Is good housekeeping the key to motor neuron survival?

Spinal muscular atrophy (SMA) is caused by a drastic reduction in the ubiquitously expressed SMN protein, which is critical for the correct assembly of the snRNP complexes required for RNA splicing. However, it is unclear why loss of SMN and altered snRNP assembly only seem to affect motor neurons. Reporting in this issue, Zhang et al. (2008) challenge prior assumptions about the housekeeping function of SMN and demonstrate that loss of SMN leads to highly tissue-specific effects on splicing.     

Does autophagy contribute to cell death?

Autophagy (specifically macroautophagy) is an evolutionarily conserved catabolic process where the cytoplasmic contents of a cell are sequestered within double membrane vacuoles, called autophagosomes, and subsequently delivered to the lysosome for degradation. Autophagy can function as a survival mechanism in starving cells. At the same time, extensive autophagy is commonly observed in dying cells, leading to its classification as an alternative form of programmed cell death. The functional contribution of autophagy to cell death has been a subject of great controversy. However, several recent loss-of-function studies of autophagy (atg) genes have begun to address the roles of autophagy in both cell death and survival. Here, we review the emerging evidence in favor of and against autophagic cell death, discuss the possible roles that autophagic degradation might play in dying cells, and identify salient issues for future investigation.     

Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death

Inclusions composed of α-synuclein (α-syn), i.e., Lewy bodies (LBs) and Lewy neurites (LNs), define synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Here, we demonstrate that preformed fibrils generated from full-length and truncated recombinant α-syn enter primary neurons, probably by adsorptive-mediated endocytosis, and promote recruitment of soluble endogenous α-syn into insoluble PD-like LBs and LNs. Remarkably, endogenous α-syn was sufficient for formation of these aggregates, and overexpression of wild-type or mutant α-syn was not required. LN-like pathology first developed in axons and propagated to form LB-like inclusions in perikarya. Accumulation of pathologic α-syn led to selective decreases in synaptic proteins, progressive impairments in neuronal excitability and connectivity, and, eventually, neuron death. Thus, our data contribute important insights into the etiology and pathogenesis of PD-like α-syn inclusions and their impact on neuronal functions, and they provide a model for discovering therapeutics targeting pathologic α-syn-mediated neurodegeneration.     

Role of energy metabolic deficits and oxidative stress in excitotoxic spinal motor neuron degeneration in?vivo

MN (motor neuron) death in amyotrophic lateral sclerosis may be mediated by glutamatergic excitotoxicity. Previously, our group showed that the microdialysis perfusion of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) in the rat lumbar spinal cord induced MN death and permanent paralysis within 12 h after the experiment. Here, we studied the involvement of energy metabolic deficiencies and of oxidative stress in this MN degeneration, by testing the neuroprotective effect of various energy metabolic substrates and antioxidants. Pyruvate, lactate, β-hydroxybutyrate, α-ketobutyrate and creatine reduced MN loss by 50–65%, preserved motor function and completely prevented the paralysis. Ascorbate, glutathione and glutathione ethyl ester weakly protected against motor deficits and reduced MN death by only 30–40%. Reactive oxygen species formation and 3-nitrotyrosine immunoreactivity were studied 1.5–2 h after AMPA perfusion, during the initial MN degenerating process, and no changes were observed. We conclude that mitochondrial energy deficiency plays a crucial role in this excitotoxic spinal MN degeneration, whereas oxidative stress seems a less relevant mechanism. Interestingly, we observed a clear correlation between the alterations of motor function and the number of damaged MNs, suggesting that there is a threshold of about 50% in the number of healthy MNs necessary to preserve motor function.     

Many ways to exit? Cell death categories in plants

Programmed cell death (PCD) is an integral part of plant development and defence. It occurs at all stages of the life cycle, from fertilization of the ovule to death of the whole plant. Without it, tall trees would probably not be possible and plants would more easily succumb to invading microorganisms. Here, we have attempted to categorize plant PCD in relation to three established morphological types of metazoan cell death: apoptosis, autophagy and non-lysosomal PCD. We conclude that (i) no examples of plant PCD conform to the apoptotic type, (ii) many examples of PCD during plant development agree with the autophagic type, and (iii) that other examples are apparently neither apoptotic nor autophagic.     

Analysis of cause of death: Competing risks or progressive illness‐death model?

The analysis of cause of death is increasingly becoming a topic in oncology. It is usually distinguished between disease‐related and disease‐unrelated death. A frequently used approach is to define death as disease‐related when a progression to advanced phases has occurred before, otherwise as disease‐unrelated. The data are often analyzed as competing risks, while a progressive illness‐death model might in fact describe the situation more precisely. In this study, we investigated under which circumstances this misspecification leads to biased estimations of the state occupation probabilities. We simulated data according to the progressive illness‐death model in various settings, analyzed them with a competing risks model and with a progressive illness‐death model and compared them to the true state occupation probabilities. Censoring was either added independently of the status or based on the patients' status. The simulations showed that the censoring mechanism was decisive for the bias while neither the progression hazard nor the Markov property was important. Further, we found a slightly increased standard deviation for the competing risk estimator when censoring was independent of the patients' status. For illustration, both methods were applied to two practical examples of chronic myeloid leukemia (CML): one randomized controlled trial and one registry data set. While in the first case both estimators yielded almost identical results, in the latter case, visible differences were found between both methods.     

VEGF: necessary to prevent motoneuron degeneration, sufficient to treat ALS?

Since Charcot recognized the devastating disorder amyotrophic lateral sclerosis (ALS) in 1874, many theories have been proposed to explain its pathogenesis, but it remains as deadly and incurable as ever. Three years ago it was reported that reduced levels of vascular endothelial growth factor (VEGF) caused ALS-like motoneuron degeneration in mice. Recent evidence indicates that insufficient VEGF is also a risk factor for ALS in humans. Although VEGF was once considered to be only a specific angiogenic factor, emerging evidence indicates that it also displays important neuroprotective activity. These insights have primed widespread interest in developing VEGF-based therapies for (moto)neuron degenerative disorders, raising new hope for the treatment of ALS and other neurodegenerative diseases.     

Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9

Background

Frontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND.

Methods

Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing.

Results

Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree.

Conclusion

Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.     

Howler monkey tolerance to habitat shrinking: Lifetime warranty or death sentence?

Habitat loss and fragmentation are major threats to the conservation of nonhuman primates. Given that species differ in their responses to fragmented landscapes, identifying the factors that enable them to cope with altered environments or that cause their extirpation is critical to design conservation management strategies. Howler monkeys (Alouatta spp.) are good models for studying the strategies of tolerant arboreal taxa and how they cope with spatial restriction, because they live in habitats ranging from vast pristine forests to small disturbed fragments and orchards. While some aspects of their ecology and behavior are conserved, others vary in predictable ways in response to habitat shrinking and decreasing resource availability. We argue that the ability of individual howler monkeys to inhabit low-quality environments does not guarantee the long-term persistence of the small populations that live under these conditions. Their local extirpation explains why few forest fragments below a given area threshold are frequently inhabited in landscapes where recolonization and gene flow are compromised by long isolation distances or less permeable matrices. In sum, howlers’ ability to cope with habitat restriction at the individual level in the short-term may mask the inevitable fate of isolated populations, thereby compromising the persistence of the species at a regional scale in the long-term if howlers’ need for protection in large forests is undervalued.     

Targeting hIAPP fibrillation: A new paradigm to prevent β-cell death?

Loss of pancreatic β-cell mass is deleterious for type 2 diabetes patients since it reduces insulin production, critical for glucose homeostasis. The main research axis developed over the last few years was to generate new pancreatic β-cells or to transplant pancreatic islets as occurring for some specific type 1 diabetes patients. We evaluate here a new paradigm consisting in preservation of β-cells by prevention of human islet amyloid polypeptide (hIAPP) oligomers and fibrils formation leading to pancreatic β-cell death. We review the hIAPP physiology and the pathology that contributes to β-cell destruction, deciphering the various cellular steps that could be involved. Recent progress in understanding other amyloidosis such as Aβ, Tau, α-synuclein or prion, involved in neurodegenerative processes linked with inflammation, has opened new research lines of investigations to preserve neuronal cells. We evaluate and estimate their transposition to the pancreatic β-cells preservation. Among them is the control of reactive oxygen species (ROS) production occurring with inflammation and the possible implication of the mitochondrial translocator protein as a diagnostic and therapeutic target. The present review also focuses on other amyloid forming proteins from molecular to physiological and physiopathological points of view that could help to better decipher hIAPP-induced β-cell death mechanisms and to prevent hIAPP fibril formation.     

Giant cell formation: the way to cell death or cell survival?

The study of giant cells in populations of different tumor cells and evaluation of their role in cancer development is an expanding field. The formation of giant cells has been shown to be followed by mitotic catastrophe, apoptosis, necrosis, and other types of cell elimination. Reports also demonstrate that giant cells can escape cell death and give rise to new cancer cells. However, it is not known if the programmed cell death is involved in this type of cell cycle disorders. Here we describe principal events that are observed during giant cell formation. We also consider the role of giant cells in cancer development, taking into account both published work and our own recent data in this field.     

Transglutaminase inhibition: A therapy to protect cells from death in neurodegeneration?

Transglutaminases(TGs;E.C.2.3.2.13)are ubiquitous enzymes which catalyze post-translational modifications of proteins.TGs and TG-catalyzed post-translational modifications of proteins have been shown to be involved in the molecular mechanisms responsible for several human diseases.In particular,TG activity has been hypothesized to also be involved also in the molecular mechanisms responsible for human neurodegenerative diseases.In support of this hypothesis,Basso et al recently demonstrated that the TG inhibition protects against oxidative stress-induced neuronal death,suggesting that multiple TG isoforms participate in oxidative stress-induced cell death and that nonselective TG isoform inhibitors will be most effective in fighting oxidative death in neurological disorders.In this commentary,we discuss the possible molecular mechanisms by which TG activity could be involved in the pathogenesis of neurological diseases,with particular reference to neurodegenerative diseases,and the possible involvement of multiple TG isoforms expressed simultaneously in the nervous system in these diseases.Moreover,therapeutic strategies based on the use of selective or nonselective TG inhibitors for the amelioration of thesymptoms of patients with neurological diseases,characterized by aberrant TG activity,are also discussed.