Showing papers on "Neurodegeneration published in 2005"
TL;DR: Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
Abstract: Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
2,146 citations
TL;DR: The biochemical isolation of discrete amyloid-β moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.
Abstract: A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-β protein interferes with cognitive function. Soluble oligomeric forms of amyloid-β, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although β-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-β moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.
1,719 citations
TL;DR: It is found that application of amyloid-β promoted endocytosis of NMDA receptors in cortical neurons, indicating a new mechanism by which amyloids-β can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
Abstract: Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
1,442 citations
TL;DR: Evidence supports that the unregulated activation of microglia in response to environmental toxins, endogenous proteins, and neuronal death results in the production of toxic factors that propagate neuronal injury.
1,405 citations
TL;DR: The present work demonstrates extensive abnormalities in insulin and insulin-like growth factor type I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system neurons, the expression levels are markedly reduced in AD.
Abstract: The neurodegeneration that occurs in sporadic Alzheimer's disease (AD) is consistently associated with a number of characteristic histopathological, molecular, and biochemical abnormalities, including cell loss, abundant neurofibrillary tangles and dystrophic neurites, amyloid-beta deposits, increased activation of pro-death genes and signaling pathways, impaired energy metabolism/mitochondrial function, and evidence of chronic oxidative stress. The general inability to convincingly link these phenomena has resulted in the emergence and propagation of various heavily debated theories that focus on the role of one particular element in the pathogenesis of all other abnormalities. However, the accumulating evidence that reduced glucose utilization and deficient energy metabolism occur early in the course of disease, suggests a role for impaired insulin signaling in the pathogenesis of AD. The present work demonstrates extensive abnormalities in insulin and insulin-like growth factor type I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system (CNS) neurons, the expression levels are markedly reduced in AD. These abnormalities were associated with reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA, IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt (activated), and increased glycogen synthase kinase-3beta activity and amyloid precursor protein mRNA expression. The strikingly reduced CNS expression of genes encoding insulin, IGF-I, and IGF-II, as well as the insulin and IGF-I receptors, suggests that AD may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes mellitus. Therefore, we propose the term, "Type 3 Diabetes" to reflect this newly identified pathogenic mechanism of neurodegeneration.
1,348 citations
TL;DR: Changing attention is being focused on alternative signaling pathways leading to cell death including necrosis, autophagy, and mitotic catastrophe.
Abstract: Apoptosis plays an important role in development and maintenance of tissue homeostasis. Intensive efforts have been made to explore the molecular mechanisms of the apoptotic signaling pathways including the initiation, mediation, execution and regulation of apoptosis. Caspases are central effectors of apoptosis. Cells undergo apoptosis through two major pathways, namely the extrinsic pathway (death receptor pathway) or the intrinsic pathway (the mitochondrial pathway). Finally, the contents of dead cells are packaged into apoptotic bodies, which are recognized by neighboring cells or macrophages and cleared by phagocytosis. Cellular apoptosis is tightly controlled by a complex regulatory networks including balancing pro-survival signals. De-regulation of apoptosis may lead to pathological disorders such as developmental defects, autoimmune diseases, neurodegeneration or cancer. Increasing attention is being focused on alternative signaling pathways leading to cell death including necrosis, autophagy, and mitotic catastrophe. Understanding of cell death signaling pathways is relevant to understanding cancer and to developing more effective therapeutics.
1,283 citations
TL;DR: The results suggest that nigral neuronal damage, regardless of etiology, may release aggregated α‐synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD.
Abstract: A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson's disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of alpha-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human alpha-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated alpha-synuclein. Furthermore, microglial enhancement of alpha-synuclein-mediated neurotoxicity depended on phagocytosis of alpha-synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of etiology, may release aggregated alpha-synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in alpha-synuclein-mediated microglial activation and associated neurotoxicity.
1,097 citations
TL;DR: It is proposed that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades.
Abstract: Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and polyglutamine diseases. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.
1,020 citations
TL;DR: Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.
927 citations
TL;DR: There is now extensive evidence to support the direct involvement of interleukin-1 in the neuronal injury that occurs in both acute and chronic neurodegenerative disorders, and a rationale for targeting the interleuko-1 system as a therapeutic strategy is provided.
Abstract: Interleukin-1 is a pro-inflammatory cytokine that has numerous biological effects, including activation of many inflammatory processes (through activation of T cells, for example), induction of expression of acute-phase proteins, an important function in neuroimmune responses and direct effects on the brain itself. There is now extensive evidence to support the direct involvement of interleukin-1 in the neuronal injury that occurs in both acute and chronic neurodegenerative disorders. This article discusses the key evidence of a role for interleukin-1 in acute neurodegeneration - for example, stroke and brain trauma - and provides a rationale for targeting the interleukin-1 system as a therapeutic strategy.
917 citations
TL;DR: There is strong evidence from genetics and transgenic mouse models that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Alzheimer’s disease, Parkinson's disease, Huntington's Disease, amyotrophic lateral sclerosis, hereditary spastic paraplegia, and cerebellar degenerations.
Abstract: A critical role of mitochondrial dysfunction and oxidative damage has been hypothesized in both aging and neurodegenerative diseases. Much of the evidence has been correlative, but recent evidence has shown that the accumulation of mitochondrial DNA mutations accelerates normal aging, leads to oxidative damage to nuclear DNA, and impairs gene transcription. Furthermore, overexpression of the antioxidant enzyme catalase in mitochondria increases murine life span. There is strong evidence from genetics and transgenic mouse models that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hereditary spastic paraplegia, and cerebellar degenerations. Therapeutic approaches targeting mitochondrial dysfunction and oxidative damage in these diseases therefore have great promise.
TL;DR: A powerful in vivo activity of α-synuclein is revealed in protecting nerve terminals against injury and it is suggested that this activity operates in conjunction with CSPα and SNARE proteins on the presynaptic membrane interface.
TL;DR: It is shown that a small percentage of newly synthesized α-syn is rapidly secreted from cells via unconventional, endoplasmic reticulum/Golgi-independent exocytosis and this finding proves that intravesicular localization and secretion are part of normal life cycle of α- syn and might also contribute to pathological function of this protein.
Abstract: α-Synuclein (α-syn), particularly in its aggregated forms, is implicated in the pathogenesis of Parkinson's disease and other related neurological disorders. However, the normal biology of α-syn and how it relates to the aggregation of the protein are not clearly understood. Because of the lack of the signal sequence and its predominant localization in the cytosol, α-syn is generally considered exclusively an intracellular protein. Contrary to this assumption, here, we show that a small percentage of newly synthesized α-syn is rapidly secreted from cells via unconventional, endoplasmic reticulum/Golgi-independent exocytosis. Consistent with this finding, we also demonstrate that a portion of cellular α-syn is present in the lumen of vesicles. Importantly, the intravesicular α-syn is more prone to aggregation than the cytosolic protein, and aggregated forms of α-syn are also secreted from cells. Furthermore, secretion of both monomeric and aggregated α-syn is elevated in response to proteasomal and mitochondrial dysfunction, cellular defects that are associated with Parkinson's pathogenesis. Thus, intravesicular localization and secretion are part of normal life cycle of α-syn and might also contribute to pathological function of this protein.
TL;DR: What the authors believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone, and paraquat are discussed.
Abstract: Parkinson's disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. It results mainly from the death of dopaminergic neurons in the substantia nigra. PD etiology remains mysterious, whereas its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. Most insights into PD pathogenesis come from investigations performed in experimental models of PD, especially those produced by neurotoxins. Although a host of natural and synthetic molecules do exert deleterious effects on dopaminergic neurons, only a handful are used in living laboratory animals to recapitulate some of the hallmarks of PD. In this review, we discuss what we believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. The main goal is to provide an updated summary of the main characteristics of each of these four neurotoxins. However, we also try to provide the reader with an idea about the various strengths and the weaknesses of these neurotoxic models.
TL;DR: This review draws together and summarize information from many laboratories about the characteristics of the individual mutant SOD1 proteins in vivo and in vitro in the hope that it will aid investigators in their search for the cause(s) of S OD1-associated fALS.
Abstract: Copper-zinc superoxide dismutase (CuZnSOD, SOD1 protein) is an abundant copper- and zinc-containing protein that is present in the cytosol, nucleus, peroxisomes, and mitochondrial intermembrane space of human cells. Its primary function is to act as an antioxidant enzyme, lowering the steady-state concentration of superoxide, but when mutated, it can also cause disease. Over 100 different mutations have been identified in the sod1 genes of patients diagnosed with the familial form of amyotrophic lateral sclerosis (fALS). These mutations result in a highly diverse group of mutant proteins, some of them very similar to and others enormously different from wild-type SOD1. Despite their differences in properties, each member of this diverse set of mutant proteins causes the same clinical disease, presenting a challenge in formulating hypotheses as to what causes SOD1-associated fALS. In this review, we draw together and summarize information from many laboratories about the characteristics of the individual mutant SOD1 proteins in vivo and in vitro in the hope that it will aid investigators in their search for the cause(s) of SOD1-associated fALS.
TL;DR: It is demonstrated that NF-κB signaling in microglia is critically involved in neuronal death induced by amyloid-β (Aβ) peptides, which are widely presumed to cause Alzheimer disease, and SIRT1 is implicate in this pathway.
TL;DR: Both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death, and the finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.
Abstract: The contribution of inflammation to the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are “primed” to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1β (IL-1β) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in prion-diseased mice than in control mice and induced microglial expression of IL-1β. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.
TL;DR: Characterizes the abnormalities in insulin and IGF gene expression and receptor binding in brains with different Braak stage severities of AD and provides further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus and progresses with severity of neurodegeneration.
Abstract: Reduced glucose utilization and energy metabolism occur early in the course of Alzheimer's disease (AD) and correlate with impaired cognition. Glucose utilization and energy metabolism are regulated by insulin and insulin-like growth factor I (IGF-I), and correspondingly, studies have shown that cognitive impairment may be improved by glucose or insulin administration. Recently, we demonstrated significantly reduced levels of insulin and IGF-I polypeptide genes and their corresponding receptors in advanced AD relative to aged control brains. The abnormalities in gene expression were accompanied by impaired survival signaling downstream through PI3 kinase-Akt. The present work characterizes the abnormalities in insulin and IGF gene expression and receptor binding in brains with different Braak stage severities of AD. Realtime quantitative RT-PCR analysis of frontal lobe tissue demonstrated that increasing AD Braak Stage was associated with progressively reduced levels of mRNA corresponding to insulin, IGF-I, and IGF-II polypeptides and their receptors, tau, which is regulated by insulin and IGF-I, and the Hu D neuronal RNA binding protein. In contrast, progressively increased levels of amyloid beta protein precursor (AbetaPP), glial fibrillary acidic protein, and the IBA1/AIF1 microglial mRNA transcripts were detected with increasing AD Braak Stage. Impairments in growth factor and growth factor receptor expression and function were associated with increasing AD Braak stage dependent reductions in insulin, IGF-I, and IGF-II receptor binding, ATP levels, and choline acetyltransferase (ChAT) expression. Further studies demonstrated that: 1) ChAT expression increases with insulin or IGF-I stimulation; 2) ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons; and 3) ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD. Together, these data provide further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus (? Type 3) and progresses with severity of neurodegeneration.
TL;DR: Evidence of oxidative stress in aging brain, some of the most important neurodegenerative diseases, and in two common and highly disabling vascular pathologies--stroke and cardiac failure are reviewed.
TL;DR: It is suggested that protein aggregation is pathogenic, but several lines of evidence indicate that inclusion bodies are not the main cause of toxicity, and probably represent a cellular protective response.
Abstract: Neurodegenerative diseases typically involve deposits of inclusion bodies that contain abnormal aggregated proteins. Therefore, it has been suggested that protein aggregation is pathogenic. However, several lines of evidence indicate that inclusion bodies are not the main cause of toxicity, and probably represent a cellular protective response. Aggregation is a complex multi-step process of protein conformational change and accretion. The early species in this process might be most toxic, perhaps through the exposure of buried moieties such as main chain NH and CO groups that could serve as hydrogen bond donors or acceptors in abnormal interactions with other cellular proteins. This model implies that the pathogenesis of diverse neurodegenerative diseases arises by common mechanisms, and might yield common therapeutic targets.
TL;DR: SorLA acts as a sorting receptor that protects APP from processing into Abeta and thereby reduces the burden of amyloidogenic peptide formation and may increase Abeta production and plaque formation and promote spontaneous AD.
Abstract: sorLA (Sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid beta-peptide (Abeta), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to Abeta, whereas ablation of sorLA expression in knockout mice results in increased levels of Abeta in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into Abeta and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase Abeta production and plaque formation and promote spontaneous AD.
TL;DR: The role of phosphorylation of Ser129 in α-synuclein toxicity and inclusion formation is defined using a Drosophila model of Parkinson disease to show that increased number of inclusion bodies correlates with reduced toxicity, and inclusion bodies may protect neurons from α- synucleinoxicity.
Abstract: α-Synuclein is phosphorylated at serine 129 (Ser129) in intracellular protein aggregates called Lewy bodies. These inclusion bodies are the characteristic pathologic lesions of Parkinson disease. Here we define the role of phosphorylation of Ser129 in α-synuclein toxicity and inclusion formation using a Drosophila model of Parkinson disease. Mutation of Ser129 to alanine to prevent phosphorylation completely suppresses dopaminergic neuronal loss produced by expression of human α-synuclein. In contrast, altering Ser129 to the negatively charged residue aspartate, to mimic phosphorylation, significantly enhances α-synuclein toxicity. The G protein–coupled receptor kinase 2 (Gprk2) phosphorylates Ser129 in vivo and enhances α-synuclein toxicity. Blocking phosphorylation at Ser129 substantially increases aggregate formation. Thus Ser129 phosphorylation status is crucial in mediating α-synuclein neurotoxicity and inclusion formation. Because increased number of inclusion bodies correlates with reduced toxicity, inclusion bodies may protect neurons from α-synuclein toxicity.
TL;DR: Normal age-related glial changes, likely a response to the normal wear and tear of the aging process, raise the threshold of glial activation and thus may explain the fact that even genetically determined Alzheimer's disease only shows the full manifestation of the disease decades after birth.
TL;DR: A novel transgenic mouse that closely mimics human tauopathy is described and may represent an important model for the future study of tau-related neurodegenerative disease.
Abstract: Here, we describe the generation of a novel transgenic mouse model of human tauopathy. The rTg(tauP301L)4510 mouse expresses the P301L mutation in tau (4R0N) associated with frontotemporal dementia and parkinsonism linked to chromosome 17. Transgene expression was driven by a forebrain-specific Ca2+ calmodulin kinase II promoter system resulting in high levels of expression in the hippocampus and neocortex. Importantly, transgene expression in this model is induced via the tetracycline-operon responsive element and is suppressed after treatment with doxycycline. Continued transgene expression in rTg(tauP301L)4510 mice results in age-dependent development of many salient characteristics of hereditary human dementia. From an early age, immunohistochemical studies demonstrated abnormal biochemical processing of tau and the presence of pathological conformation- and phosphorylation-dependent epitopes. Neurofibrillary tangle (NFT) pathology was first observed in the neocortex and progressed into the hippocampus and limbic structures with increasing age. Consistent with the formation of NFTs, immunoblots indicated an age-dependent transition of accumulating tau species from Sarkosyl soluble 55 kDa to insoluble hyperphosphorylated 64 kDa. Ultrastructural analysis revealed the presence of straight tau filaments. Furthermore, the effects of tauP301L expression on spatial reference memory were longitudinally tested using the Morris water maze. Compared with nontransgenic age-matched control littermates, rTg(tauP301L)4510 mice developed significant cognitive impairments from 4 months of age. Memory deficits were accompanied by gross forebrain atrophy and a prominent loss of neurons, most strikingly in hippocampal subdivision CA1. Collectively, these data describe a novel transgenic mouse that closely mimics human tauopathy and may represent an important model for the future study of tau-related neurodegenerative disease.
TL;DR: Inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury in mammals, and inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain.
Abstract: Rho kinases (ROCKs), the first Rho effectors to be described, are serine/threonine kinases that are important in fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho/ROCK pathway has been observed in various disorders of the central nervous system. Injury to the adult vertebrate brain and spinal cord activates ROCKs, thereby inhibiting neurite growth and sprouting. Inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury in mammals, and inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain. ROCK inhibitors therefore have potential for preventing neurodegeneration and stimulating neuroregeneration in various neurological disorders.
TL;DR: It is suggested that vaccination is effective in reducing neuronal accumulation of halpha-syn aggregates and that further development of this approach might have a potential role in the treatment of LBD.
TL;DR: The results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology.
Abstract: Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/ HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P < 0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/ HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.
TL;DR: These data are the first to show a substantial extension of survival in an animal model of a fatal, dominantly inherited neurodegenerative condition using RNAi and provide the highest therapeutic efficacy observed in this field to date.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the selective death of motor neurons in the brain and spinal cord. Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1). The emergence of interfering RNA (RNAi) for specific gene silencing could be therapeutically beneficial for the treatment of such dominantly inherited diseases. We generated a lentiviral vector to mediate expression of RNAi molecules specifically targeting the human SOD1 gene (SOD1). Injection of this vector into various muscle groups of mice engineered to overexpress a mutated form of human SOD1 (SOD1(G93A)) resulted in an efficient and specific reduction of SOD1 expression and improved survival of vulnerable motor neurons in the brainstem and spinal cord. Furthermore, SOD1 silencing mediated an improved motor performance in these animals, resulting in a considerable delay in the onset of ALS symptoms by more than 100% and an extension in survival by nearly 80% of their normal life span. These data are the first to show a substantial extension of survival in an animal model of a fatal, dominantly inherited neurodegenerative condition using RNAi and provide the highest therapeutic efficacy observed in this field to date.
TL;DR: Continuous low-level exposure of mice to MPTP causes a Parkinson-like syndrome in an alpha-synuclein-dependent manner, and the inhibition of the ubiquitinproteasome system and the production of inclusion bodies were reduced.
Abstract: In animals, sporadic injections of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively damage dopaminergic neurons but do not fully reproduce the features of human Parkinson's disease. We have now developed a mouse Parkinson's disease model that is based on continuous MPTP administration with an osmotic minipump and mimics many features of the human disease. Although both sporadic and continuous MPTP administration led to severe striatal dopamine depletion and nigral cell loss, we find that only continuous administration of MPTP produced progressive behavioral changes and triggered formation of nigral inclusions immunoreactive for ubiquitin and α-synuclein. Moreover, only continuous MPTP infusions caused long-lasting activation of glucose uptake and inhibition of the ubiquitin-proteasome system. In mice lacking α-synuclein, continuous MPTP delivery still induced metabolic activation, but induction of behavioral symptoms and neuronal cell death were almost completely alleviated. Furthermore, the inhibition of the ubiquitinproteasome system and the production of inclusion bodies were reduced. These data suggest that continuous low-level exposure of mice to MPTP causes a Parkinson-like syndrome in an α-synuclein-dependent manner.
TL;DR: Data show that the UPR is activated in AD, and the increased occurrence of BiP/GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the U PR early in AD neurodegeneration.
Abstract: Alzheimer's disease (AD) is, at the neuropathological level, characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR) that may protect the cell against the toxic buildup of misfolded proteins. In this study we investigated the activation of the UPR in AD. Protein levels of BiP/GRP78, a molecular chaperone which is up-regulated during the UPR, was found to be increased in AD temporal cortex and hippocampus as determined by Western blot analysis. At the immunohistochemical level intensified staining of BiP/GRP78 was observed in AD, which did not co-localize with AT8-positive neurofibrillary tangles. In addition, we performed immunohistochemistry for phosphorylated (activated) pancreatic ER kinase (p-PERK), an ER kinase which is activated during the UPR. p-PERK was observed in neurons in AD patients, but not in non-demented control cases and did not co-localize with AT8-positive tangles. Overall, these data show that the UPR is activated in AD, and the increased occurrence of BiP/GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the UPR early in AD neurodegeneration. Although the initial participation of the UPR in AD pathogenesis might be neuroprotective, sustained activation of the UPR in AD might initiate or mediate neurodegeneration.