http://www.molecularneurodegeneration.com The most accessed research articles published by Molecular Neurodegeneration 2012-04-26T00:00:00Z α-Synuclein is a small protein that has special relevance for understanding Parkinson disease and related disorders. Not only is α-synuclein found in Lewy bodies characteristic of Parkinson disease, but also mutations in the gene for α-synuclein can cause an inherited form of Parkinson disease and expression of normal α-synuclein can increase the risk of developing Parkinson disease in sporadic, or non-familial, cases. Both sporadic and familial Parkinson disease are characterized by substantial loss of several groups of neurons, including the dopaminergic cells of the substantia nigra that are the target of most current symptomatic therapies. Therefore, it is predicted that α-synuclein, especially in its mutant forms or under conditions where its expression levels are increased, is a toxic protein in the sense that it is associated with an increased rate of neuronal cell death. This review will discuss the experimental contexts in which α-synuclein has been demonstrated to be toxic. I will also outline what is known about the mechanisms by which α-synuclein triggers neuronal damage, and identify some of the current gaps in our knowledge about this subject. Finally, the therapeutic implications of toxicity of α-synuclein will be discussed. http://www.molecularneurodegeneration.com/content/4/1/9 Mark Cookson Molecular Neurodegeneration 2009, null:9 2009-02-04T00:00:00Z doi:10.1186/1750-1326-4-9 /content/figures/1750-1326-4-9-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 9 2009-02-04T00:00:00Z XML Background: Abnormal proteostasis due to alterations in protein turnover has been postulated to play acentral role in several neurodegenerative diseases. Therefore, the development of techniquesto quantify protein turnover in the brain is critical for understanding the pathogenicmechanisms of these diseases. We have developed a bolus stable isotope-labeling kinetics(SILK) technique coupled with multiple reaction monitoring mass spectrometry to measurethe clearance of proteins in the mouse brain. Results: Cohorts of mice were pulse labeled with 13 C6-leucine and the brains were isolated after predeterminedtime points. The extent of label incorporation was measured over time using massspectrometry to measure the ratio of labeled to unlabeled apolipoprotein E (apoE) andamyloid beta (Abeta). The fractional clearance rate (FCR) was then calculated by analyzing thetime course of disappearance for the labeled protein species. To validate the technique, apoEclearance was measured in mice that overexpress the low-density lipoprotein receptor(LDLR). The FCR in these mice was 2.7-fold faster than wild-type mice. To demonstrate thepotential of this technique for understanding the pathogenesis of neurodegenerative disease,we applied our SILK technique to determine the effect of ATP binding cassette A1 (ABCA1)on both apoE and Abeta clearance. ABCA1 had previously been shown to regulate both theamount of apoE in the brain, along with the extent of Abeta deposition, and represents apotential molecular target for lowering brain amyloid levels in AD patients. The FCR of apoEwas increased by 1.9- and 1.5-fold in mice that either lacked or overexpressed ABCA1,respectively. However, ABCA1 had no effect on the FCR of Abeta, suggesting that ABCA1does not regulate Abeta metabolism in the brain. Conclusions: Our SILK strategy represents a straightforward, cost-effective, and efficient method tomeasure the clearance of brain proteins in the mouse brain. We expect that this technique willbe applicable to the study of protein dynamics in the pathogenesis of severalneurodegenerative diseases, and could aid in the evaluation of novel therapeutic agents. http://www.molecularneurodegeneration.com/content/7/1/14 Jacob Basak Jungsu Kim Yuriy Pyatkivskyy Kristin Wildsmith Hong Jiang Maia Parsadanian Bruce Patterson Randall Bateman David Holtzman Molecular Neurodegeneration 2012, null:14 2012-04-18T00:00:00Z doi:10.1186/1750-1326-7-14 /content/figures/1750-1326-7-14-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 14 2012-04-18T00:00:00Z PDF The amyloid precursor protein (APP) takes a central position in Alzheimer's disease (AD) pathogenesis: APP processing generates the β-amyloid (Aβ) peptides, which are deposited as the amyloid plaques in brains of AD individuals; Point mutations and duplications of APP are causal for a subset of early onset of familial Alzheimer's disease (FAD). Not surprisingly, the production and pathogenic effect of Aβ has been the central focus in AD field. Nevertheless, the biological properties of APP have also been the subject of intense investigation since its identification nearly 20 years ago as it demonstrates a number of interesting putative physiological roles. Several attractive models of APP function have been put forward recently based on in vitro biochemical studies. Genetic analyses of gain- and loss-of-function mutants in Drosophila and mouse have also revealed important insights into its biological activities in vivo. This article will review the current understanding of APP physiological functions. http://www.molecularneurodegeneration.com/content/1/1/5 Hui Zheng Edward Koo Molecular Neurodegeneration 2006, null:5 2006-07-03T00:00:00Z doi:10.1186/1750-1326-1-5 /content/figures/1750-1326-1-5-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 5 2006-07-03T00:00:00Z XML Background: Glutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative stress and may underlie the pathophysiology of both diseases. GSTO polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, GSTO1 rs4925 and GSTO2 rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects). Results: We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 x 10-11-1.9 x 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003). Conclusion: These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases. http://www.molecularneurodegeneration.com/content/7/1/13 Mariet Allen Fanggeng Zou High Seng Chai Curtis Younkin Richard Miles Asha Nair Julia Crook V Shane Pankratz Minerva Carrasquillo Christopher Rowley Thuy Nguyen Li Ma Kimberly Malphrus Gina Bisceglio Alexandra Ortolaza Ryan Palusak Sumit Middha Sooraj Maharjan Constantin Georgescu Debra Schultz Fariborz Rakhshan Christopher Kolbert Jin Jen Sigrid Sando Jan Aasly Maria Barcikowska Ryan Uitti Zbigniew Wszolek Owen Ross Ronald Petersen Neill Graff-Radford Dennis Dickson Steven Younkin Nilufer Ertekin-Taner Molecular Neurodegeneration 2012, null:13 2012-04-11T00:00:00Z doi:10.1186/1750-1326-7-13 /content/figures/1750-1326-7-13-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 13 2012-04-11T00:00:00Z PDF Background: A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is aninhibitor of amyloid-beta precursor protein (APP) processing, which is genetically linked toAlzheimer's disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 proteinand to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by beta-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD(FDDKI). beta-cleavage of APP yields the beta-carboxyl-terminal (beta-CTF) and the amino-terminalsolubleAPPbeta (sAPPbeta) fragments. gamma-secretase processing of beta-CTF generates Abeta, which isconsidered the main cause of AD. However, inhibiting Abeta production did not rescue thedeficits of FDDK mice, suggesting that sAPPbeta/beta-CTF, and not Abeta, are the toxic speciescausing memory loss. Results: Here, we have further analyzed the effect of gamma-secretase inhibition. We show that treatmentwith a gamma-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDDKImice. This deleterious effect on memory correlates with increased levels of the beta/alpha-CTFsAPP fragments in synaptic fractions isolated from hippocampus of FDDKI mice, which isconsistent with inhibition of gamma-secretase activity. Conclusion: This harmful effect of the GSI is in sharp contrast with a pathogenic role for Abeta, and suggeststhat the worsening of memory deficits may be due to accumulation of synaptic-toxic beta/alpha-CTFs caused by GSI treatment. However, gamma-secretase cleaves more than 40 proteins; thus, thenoxious effect of GSI on memory may dependent on inhibition of cleavage of one or more ofthese other gamma-secretase substrates. These two possibilities do not need to be mutuallyexclusive. Our results are consistent with the outcome of a clinical trial with the GSISemagacestat, which caused a worsening of cognition, and advise against targeting gamma-secretase in the therapy of AD. Overall, the data also indicate that FDDKI is a valuable mousemodel to study AD pathogenesis and predict the clinical outcome of therapeutic agents forAD. http://www.molecularneurodegeneration.com/content/7/1/19 Robert Tamayev Luciano D'Adamio Molecular Neurodegeneration 2012, null:19 2012-04-26T00:00:00Z doi:10.1186/1750-1326-7-19 /content/figures/1750-1326-7-19-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 19 2012-04-26T00:00:00Z PDF The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of β-amyloid. BACE1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. The fact that BACE1 initiates the formation of β-amyloid, and the observation that BACE1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE1 inhibition thus reducing β-amyloid and its associated toxicities. However, new data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-deficient mice. Here we review BACE1 biology, covering aspects ranging from the initial identification and characterization of this enzyme to recent data detailing the apparent dysregulation of BACE1 in Alzheimer's disease. We pay special attention to the putative function of BACE1 during healthy conditions and discuss in detail the relationship that exists between key risk factors for AD, such as vascular disease (and downstream cellular consequences), and the pathogenic alterations in BACE1 that are observed in the diseased state. http://www.molecularneurodegeneration.com/content/2/1/22 Sarah Cole Robert Vassar Molecular Neurodegeneration 2007, null:22 2007-11-15T00:00:00Z doi:10.1186/1750-1326-2-22 /content/figures/1750-1326-2-22-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 22 2007-11-15T00:00:00Z XML Background: Leucine-rich repeat kinase 2 (LRRK2) is the gene responsible for autosomal-dominantParkinson's disease (PD), PARK8, but the mechanism by which LRRK2 mutations causeneuronal dysfunction remains unknown. In the present study, we investigated for the firsttime a transgenic (TG) mouse strain expressing human LRRK2 with an I2020T mutation inthe kinase domain, which had been detected in the patients of the original PARK8 family. Results: The TG mouse expressed I2020T LRRK2 in dopaminergic (DA) neurons of the substantianigra, ventral tegmental area, and olfactory bulb. In both the beam test and rotarod test, theTG mice exhibited impaired locomotive ability in comparison with their non-transgenic(NTG) littermates. Although there was no obvious loss of DA neurons in either the substantianigra or striatum, the TG brain showed several neurological abnormalities such as a reducedstriatal dopamine content, fragmentation of the Golgi apparatus in DA neurons, and anincreased degree of microtubule polymerization. Furthermore, the tyrosine hydroxylasepositiveprimary neurons derived from the TG mouse showed an increased frequency ofapoptosis and had neurites with fewer branches and decreased outgrowth in comparison withthose derived from the NTG controls. Conclusions: The I2020T LRRK2 TG mouse exhibited impaired locomotive ability accompanied byseveral dopaminergic neuron abnormalities. The TG mouse should provide valuable clues tothe etiology of PD caused by the LRRK2 mutation. http://www.molecularneurodegeneration.com/content/7/1/15 Tatsunori Maekawa Sayuri Mori Yui Sasaki Takashi Miyajima Sadahiro Azuma Etsuro Ohta Fumiya Obata Molecular Neurodegeneration 2012, null:15 2012-04-25T00:00:00Z doi:10.1186/1750-1326-7-15 /content/figures/1750-1326-7-15-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 15 2012-04-25T00:00:00Z PDF Background: A considerable proportion of all newly generated cells in the hippocampus will die beforebecoming fully differentiated, both under normal and pathological circumstances. Thecaspase-independent apoptosis-inducing factor (AIF) has not been investigated previously inthis context. Results: Postnatal day 8 (P8) harlequin (Hq) mutant mice, expressing lower levels of AIF, and wildtype littermates were injected with BrdU once daily for two days to label newborn cells. OnP10 mice were subjected to hypoxia-ischemia (HI) and their brains were analyzed 4 h, 24 hor 4 weeks later. Overall tissue loss was 63.5% lower in Hq mice 4 weeks after HI. Shorttermsurvival (4 h and 24 h) of labeled cells in the subgranular zone was neither affected byAIF downregulation, nor by HI. Long-term (4 weeks) survival of undifferentiated, BLBPpositivestem cells was reduced by half after HI, but this was not changed by AIFdownregulation. Neurogenesis, however, as judged by BrdU/NeuN double labeling, wasreduced by half after HI in wild type mice but preserved in Hq mice, indicating that primarilyneural progenitors and neurons were protected. A wave of cell death started early after HI inthe innermost layers of the granule cell layer (GCL) and moved outward, such that 24 h afterHI dying cells could be detected in the entire GCL. Conclusions: These findings demonstrate that AIF downregulation provides not only long-term overallneuroprotection after HI, but also protects neural progenitor cells, thereby rescuinghippocampal neurogenesis. http://www.molecularneurodegeneration.com/content/7/1/17 Yanyan Sun Yu Zhang Xiaoyang Wang Klas Blomgren Changlian Zhu Molecular Neurodegeneration 2012, null:17 2012-04-25T00:00:00Z doi:10.1186/1750-1326-7-17 /content/figures/1750-1326-7-17-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 17 2012-04-25T00:00:00Z PDF The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD. http://www.molecularneurodegeneration.com/content/6/1/85 Yangling Mu Fred Gage Molecular Neurodegeneration 2011, null:85 2011-12-22T00:00:00Z doi:10.1186/1750-1326-6-85 /content/figures/1750-1326-6-85-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 85 2011-12-22T00:00:00Z XML Autophagy is the major pathway involved in the degradation of proteins and organelles, cellular remodeling, and survival during nutrient starvation. Autophagosomal dysfunction has been implicated in an increasing number of diseases from cancer to bacterial and viral infections and more recently in neurodegeneration. While a decrease in autophagic activity appears to interfere with protein degradation and possibly organelle turnover, increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival in a number of disease models. On the other hand, too much autophagic activity can be detrimental as well and lead to cell death, suggesting the regulation of autophagy has an important role in cell fate decisions. An increasing number of model systems are now available to study the role of autophagy in the central nervous system and how it might be exploited to treat disease. We will review here the current knowledge of autophagy in the central nervous system and provide an overview of the various models that have been used to study acute and chronic neurodegeneration. http://www.molecularneurodegeneration.com/content/4/1/16 Philipp Jaeger Tony Wyss-Coray Molecular Neurodegeneration 2009, null:16 2009-04-06T00:00:00Z doi:10.1186/1750-1326-4-16 /content/figures/1750-1326-4-16-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 16 2009-04-06T00:00:00Z XML