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Biomedical subjects

Mel B Feany

Publications and source records attributed to Mel B Feany.

At least 19 recordsLinked to original sources
PubMed2006

Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo.

Hyperphosphorylated forms of the microtubule-associated protein (MAP) tau accumulate in Alzheimer's disease and related tauopathies and are thought to have an important role in neurodegeneration. However, the mechanisms through which phosphorylated tau induces neurodegeneration have remained elusive. Here, we show that tau-induced neurodegeneration is associated with accumulation of filamentous actin (F-actin) and the formation of actin-rich rods in Drosophila and mouse models of tauopathy. Importantly, modulating F-actin levels genetically leads to dramatic modification of tau-induced neurodegeneration. The ability of tau to interact with F-actin in vivo and in vitro provides a molecular mechanism for the observed phenotypes. Finally, we show that the Alzheimer's disease-linked human beta-amyloid protein (Abeta) synergistically enhances the ability of wild-type tau to promote alterations in the actin cytoskeleton and neurodegeneration. These findings raise the possibility that a direct interaction between tau and actin may be a critical mediator of tau-induced neurotoxicity in Alzheimer's disease and related disorders.

Actins↗
PubMed2006

Oxidative stress mediates tau-induced neurodegeneration in Drosophila.

Markers of oxidative damage have been detected in brain tissue from patients with Alzheimer disease (AD) and other neurodegenerative disorders. These findings implicate oxidative injury in the neurodegenerative process, but whether oxidative stress is a cause or a consequence of neurotoxicity remains unclear. We used a Drosophila model of human tauopathies to investigate the role of oxidative stress in neurodegeneration. Genetic and pharmacological manipulation of antioxidant defense mechanisms significantly modified neurodegeneration in our model, suggesting that oxidative stress plays a causal role in neurotoxicity. We demonstrate that the JNK signaling pathway is activated in our model, which is in agreement with previous findings in AD tissue. Furthermore, we show that the extent of JNK activation correlates with the degree of tau-induced neurodegeneration. Finally, our findings suggest that oxidative stress acts not to promote tau phosphorylation, but to enhance tau-induced cell cycle activation. In summary, our study identifies oxidative stress as a causal factor in tau-induced neurodegeneration in Drosophila.

Alzheimer Disease↗
PubMed2006

Accelerated accumulation of misfolded prion protein and spongiform degeneration in a Drosophila model of Gerstmann-Sträussler-Scheinker syndrome.

Prion diseases are CNS disorders that can occur in sporadic, infectious, and inherited forms. Although all forms of prion disease are associated with the accumulation of pathogenic conformers of the prion protein, collectively termed PrP(Sc), the mechanisms by which PrP(Sc) molecules form and cause neuronal degeneration are unknown. Using the bipartite galactosidase-4-upstream activating sequence expression system, we generated transgenic Drosophila melanogaster heterologously expressing either wild-type (WT) or mutant, disease-associated (P101L) mouse PrP molecules in cholinergic neurons. Transgenic flies expressing neuronal P101L PrP molecules exhibited severe locomotor dysfunction and premature death as larvae and adults. These striking clinical abnormalities were accompanied by age-dependent accumulation of misfolded PrP molecules, intracellular PrP aggregates, and neuronal vacuoles. In contrast, transgenic flies expressing comparable levels of WT PrP displayed no clinical, pathological, or biochemical abnormalities. These results indicate that transgenic Drosophila expressing neuronal P101L PrP specifically exhibit several hallmark features of human Gerstmann-Sträussler-Scheinker (GSS) syndrome. Because the rates of abnormal PrP accumulation and clinical progression are highly accelerated in Drosophila compared with the rates of these processes in rodents or humans, the P101L mutant may be used for future genetic and pharmacologic studies as a novel invertebrate model of GSS.

Animals↗
PubMed2006

Connecting cell-cycle activation to neurodegeneration in Drosophila.

Studies in cell-culture systems and in postmortem tissue from human disease have suggested a connection between cell-cycle activation and neurodegeneration. The fruit fly Drosophila melanogaster has recently emerged as a powerful model system in which to model neurodegenerative diseases. Here we review work in the fly that has begun to address some of the important questions regarding the relationship between cell-cycle activation and neurodegeneration in vivo, including recent data implicating cell-cycle activation as a downstream effector of tau-induced neurodegeneration. We suggest how powerful research tools in Drosophila might be utilized to approach fundamental questions that remain.

Animals↗
PubMed2006

Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity.

Alpha-synuclein is a neuronal protein implicated genetically in Parkinson's disease. alpha-synuclein localizes to the nucleus and presynaptic nerve terminals. Here we show that alpha-synuclein mediates neurotoxicity in the nucleus. Targeting of alpha-synuclein to the nucleus promotes toxicity, whereas cytoplasmic sequestration is protective in both cell culture and transgenic Drosophila. Toxicity of alpha-synuclein can be rescued by administration of histone deacetylase inhibitors in both cell culture and transgenic flies. Alpha-synuclein binds directly to histones, reduces the level of acetylated histone H3 in cultured cells and inhibits acetylation in histone acetyltransferase assays. Alpha-synuclein mutations that cause familial Parkinson's disease, A30P and A53T, exhibit increased nuclear targeting in cell culture. These findings implicate nuclear alpha-synuclein in promoting nigrostriatal degeneration in Parkinson's disease and encourage exploration of histone deacetylase inhibitors as potential therapies for the disorder.

Acetylation↗
PubMed2006

TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model.

BACKGROUND: Previous studies have demonstrated reexpression of cell-cycle markers within postmitotic neurons in neurodegenerative tauopathies, including Alzheimer's disease (AD). However, the critical questions of whether cell-cycle activation is causal or epiphenomenal to tau-induced neurodegeneration and which signaling pathways mediate cell-cycle activation in tauopathy remain unresolved. RESULTS: Cell-cycle activation accompanies wild-type and mutant tau-induced neurodegeneration in Drosophila, and genetically interfering with cell-cycle progression substantially reduces neurodegeneration. Our data support a role for cell-cycle activation downstream of tau phosphorylation, directly preceding apoptosis. We accordingly show that ectopic cell-cycle activation leads to apoptosis of postmitotic neurons in vivo. As in AD, TOR (target of rapamycin kinase) activity is increased in our model and is required for neurodegeneration. TOR activation enhances tau-induced neurodegeneration in a cell cycle-dependent manner and, when ectopically activated, drives cell-cycle activation and apoptosis in postmitotic neurons. CONCLUSIONS: TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model, identifying TOR and the cell cycle as potential therapeutic targets in tauopathies and AD.

Animals↗
PubMed2005

Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease.

Alpha-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 alpha-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 alpha-synuclein. In contrast, altering Ser129 to the negatively charged residue aspartate, to mimic phosphorylation, significantly enhances alpha-synuclein toxicity. The G protein-coupled receptor kinase 2 (Gprk2) phosphorylates Ser129 in vivo and enhances alpha-synuclein toxicity. Blocking phosphorylation at Ser129 substantially increases aggregate formation. Thus Ser129 phosphorylation status is crucial in mediating alpha-synuclein neurotoxicity and inclusion formation. Because increased number of inclusion bodies correlates with reduced toxicity, inclusion bodies may protect neurons from alpha-synuclein toxicity.

Amino Acid Substitution↗
PubMed2005

Proliferative potential of human astrocytes.

Although a number of studies have demonstrated proliferation of nonneoplastic astrocytes in experimental animal models, the proliferative potential of human astrocytes has not been well defined. Using double-label immunohistochemistry, we identified proliferating cells with the proliferation marker MIB-1 and astrocytes with glial fibrillary acidic protein staining in human biopsy and autopsy tissue. MIB-1 labeling of astrocytes was monitored in a variety of conditions containing significant numbers of reactive astrocytes, including infections, arteriovenous malformations, demyelinating lesions, metastatic tumors, and long-standing gliosis. Twenty-nine of a total of 54 cases showed no evidence of astrocyte-specific MIB-1 labeling despite prominent reactive changes. An average proliferation rate of 0.9% was present in the remaining 25 cases. Labeling indices were highest in infectious conditions and acute demyelinating lesions. We also examined astrocyte proliferation in 5 cases of progressive multifocal leukoencephalopathy. Astrocytic labeling indices were notably elevated in these cases, with an average labeling index of 5.8%. We conclude that low, but appreciable, astrocytic proliferation may occur in nonneoplastic human astrocytes. These findings have implications for astrocyte function in the normal and disease states and for the diagnostic distinction between reactive lesions and low-grade astrocytic neoplasms.

Adult↗
PubMed2004

Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases.

Most human neurodegenerative diseases have a number of common features, including adult onset, progressive degeneration of selected neuronal populations and formation of abnormal protein aggregates. Although these shared characteristics raise the possibility of conserved pathogenic mechanisms, the diverse clinical and pathological features of each disorder indicate significant differences. As a number of human neurodegenerative diseases have now been modeled in Drosophila, and genetic modifiers identified, we have been able to perform a genetic comparison of pathways controlling toxicity in these models. By directly comparing modifiers isolated in the models of polyglutamine diseases and in a Drosophila model of tauopathy, we find a final common pathway of cell death involving apoptosis. Among the polyglutamine diseases, protein folding and histone acetylation are common key mediators. In addition, two novel modifiers suggest shared pathways of toxicity among all the disorders. Cell-type specificity is a salient feature of all neurodegenerative diseases; however, most work to date in the Drosophila models have been performed in the retina. Therefore, we determined whether similar pathways of toxicity operate in neurons of the Drosophila brain. Many, but not all, retinal modifiers also modify toxicity in postmitotic neurons in the brain. Analysis of polyglutamine toxicity in the adult brain facilitated the identification of nicotinamide (vitamin B3), a vitamin with histone deacetylase inhibiting activity, as a potent suppressor of polyglutamine toxicity. These findings outline common pathways of neurotoxicity, demonstrate disease- and cell-type specific pathways and identify a common vitamin as a potential therapy in polyglutamine disorders.

Animals↗
PubMed2003

Polyglutamines stop traffic: axonal transport as a common target in neurodegenerative diseases.

In this issue of Neuron, two papers provide evidence that polyglutamine (polyQ) proteins disrupt axonal transport. Gunawardena et al. show that normal levels of huntingtin are required for proper axonal transport in Drosophila. In addition, expression of expanded polyQ proteins disrupts axonal transport in larval neurons. Szebenyi and colleagues find that polyQ proteins directly inhibit fast axonal transport using axoplasm from the squid giant axon and suggest that axonal transport defects may be a common feature of polyQ disease pathogenesis.

Animals↗
PubMed2003

Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease.

Transgenic Drosophila expressing human alpha-synuclein faithfully replicate essential features of human Parkinson's disease, including age-dependent loss of dopaminergic neurons, Lewy-body-like inclusions and locomotor impairment. To define the transcriptional program encoding molecular machinery involved in alpha-synuclein pathology, we characterized expression of the entire Drosophila genome at pre-symptomatic, early and advanced disease stages. Fifty-one signature transcripts, including lipid, energy and membrane transport mRNAs, were tightly associated with alpha-synuclein expression. Most importantly, at the pre-symptomatic stage, when the potential for neuroprotection is greatest, expression changes revealed specific pathology. In age-matched tau transgenic Drosophila, the transcription of alpha-synuclein associated genes was normal, suggesting highly distinct pathways of neurodegeneration. Temporal profiling of progressive gene expression changes in neurodegenerative disease models provides unbiased starting points for defining disease mechanisms and for identifying potential targets for neuroprotective drugs at pre-clinical stages.

Animals↗
PubMed2003

Parkin: a multipurpose neuroprotective agent?

An autosomal recessive juvenile-onset form of Parkinson's disease (AR-JP) is caused by loss-of-function mutations of the parkin gene, which encodes a ubiquitin-protein ligase. Three recent reports demonstrate that parkin can protect neurons from diverse cellular insults, including alpha-synuclein toxicity, proteasomal dysfunction, Pael-R accumulation, and kainate-induced excitotoxicity. These findings suggest a central role for parkin in maintaining dopaminergic neuronal integrity and strengthen the link between AR-JP and the more common sporadic form of Parkinson's disease.

Animals↗
PubMed2003

Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Several lines of evidence strongly implicate mitochondrial dysfunction as a major causative factor in PD, although the molecular mechanisms responsible for mitochondrial dysfunction are poorly understood. Recently, loss-of-function mutations in the parkin gene, which encodes a ubiquitin-protein ligase, were found to underlie a familial form of PD known as autosomal recessive juvenile parkinsonism (AR-JP). To gain insight into the molecular mechanism responsible for selective cell death in AR-JP, we have created a Drosophila model of this disorder. Drosophila parkin null mutants exhibit reduced lifespan, locomotor defects, and male sterility. The locomotor defects derive from apoptotic cell death of muscle subsets, whereas the male sterile phenotype derives from a spermatid individualization defect at a late stage of spermatogenesis. Mitochondrial pathology is the earliest manifestation of muscle degeneration and a prominent characteristic of individualizing spermatids in parkin mutants. These results indicate that the tissue-specific phenotypes observed in Drosophila parkin mutants result from mitochondrial dysfunction and raise the possibility that similar mitochondrial impairment triggers the selective cell loss observed in AR-JP.

Amino Acid Sequence↗
PubMed2003

Post-transcriptional suppression of pathogenic prion protein expression in Drosophila neurons.

A wealth of evidence supports the view that conformational change of the prion protein, PrPC, into a pathogenic isoform, PrPSc, is the hallmark of sporadic, infectious, and inherited forms of prion disease. Although the central role played by PrPSc in the pathogenesis of prion disease is appreciated, the cellular mechanisms that recognize PrPSc and modulate its production, clearance, and neural toxicity have not been elucidated. To address these questions, we used a tissue-specific expression system to express wild-type and disease-associated PrP molecules heterologously in Drosophila melanogaster. Our results indicate that Drosophila brain possesses a specific and saturable mechanism that suppresses the accumulation of PG14, a disease-associated insertional PrP mutant. We also found that wild-type PrP molecules are maintained in a detergent-soluble conformation throughout life in Drosophila brain neurons, whereas they become detergent-insoluble in retinal cells as flies age. PG14 protein expression in Drosophila eye did not cause retinal pathology. Our work reveals the presence of mechanisms in neurons that specifically counterbalance the production of misfolded PrP conformations, and provides an opportunity to study these processes in a model organism amenable to genetic analysis.

Age Factors↗
PubMed2003

Genetic modifiers of tauopathy in Drosophila.

In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

Alzheimer Disease↗