1,065 research outputs found
Defective phagocytic corpse processing results in neurodegeneration and can be rescued by TORC1 activation
This work was supported by NIH Grants R01 GM094452 (K.M.) and F31 GM099425 (J.I.E.), BU Alzheimer's Disease Core Center NIH Grant P30 AG13846, Boston University Undergraduate Research Opportunities Program grants (J.A.T., V.S.), and NIH Grant R01 AG044113 to M.B.F. We thank the Bloomington Stock Center, TRiP at Harvard Medical School, the Kyoto Drosophila Genetic Resource Center, Estee Kurant, Eric Baehrecke, Marc Freeman, and Mary Logan for fly strains. We thank Todd Blute for assistance with electron microscopy and the Developmental Studies Hybridoma Bank for antibodies. (R01 GM094452 - NIH; F31 GM099425 - NIH; R01 AG044113 - NIH; P30 AG13846 - BU Alzheimer's Disease Core Center NIH Grant; Boston University Undergraduate Research Opportunities Program)https://www.jneurosci.org/content/36/11/3170.longPublished versionPublished versio
Parkinson's Disease-Related Protein, Ξ±-Synuclein, in Malignant Melanoma
BACKGROUND: Melanoma is the major cause of skin cancer death worldwide. Parkinson's disease is a neurodegenerative disorder that is caused by mutation of alpha-synuclein or other genes. Importantly, epidemiological studies have reported co-occurrence of melanoma and Parkinson's disease, suggesting that these two diseases could share common genetic components. METHODOLOGY/PRINCIPAL FINDINGS: Recently, we found that human melanoma cell lines highly express alpha-synuclein, whereas the protein is undetectable in the non-melanoma cancer cell lines tested. To investigate the expression of alpha-synuclein in human melanoma tissues, we immunostained sections of melanoma, nevus, non-melanocytic cutaneous carcinoma, and normal skin. alpha-Synuclein was positively detected in 86% of the primary and 85% of the metastatic melanoma sections, as well as in 89% of nevus sections. However, alpha-synuclein was undetectable in non-melanocytic cutaneous carcinoma and normal skin. CONCLUSIONS/SIGNIFICANCE: The Parkinson's disease-related protein, alpha-synuclein, is expressed in both malignant and benign melanocytic lesions, such as melanomas and nevi. Although alpha-synuclein cannot be used to distinguish between malignant and benign melanocytic skin lesions, it might be a useful biomarker for the diagnosis of metastatic melanoma
The Unfolded Protein Response Protects from Tau Neurotoxicity In Vivo
The unfolded protein response is a critical system by which the cell handles excess misfolded protein in the secretory pathway. The role of the system in modulating the effects of aggregation prone cytosolic proteins has received less attention. We use genetic reporters to demonstrate activation of the unfolded protein response in a transgenic Drosophila model of Alzheimer's disease and related tauopathies. We then use loss of function genetic reagents to support a role for the unfolded protein response in protecting from tau neurotoxicity. Our findings suggest that the unfolded protein response can ameliorate the toxicity of tau in vivo
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Tau promotes neurodegeneration through global chromatin relaxation
The microtubule-associated protein tau is involved in a number of neurodegenerative disorders, including Alzheimerβs disease (AD). Previous studies link oxidative stress and subsequent DNA damage to neuronal death in AD and related tauopathies. Since DNA damage can significantly alter chromatin structure, we examined epigenetic changes in tau-induced neurodegeneration. We have found widespread loss of heterochromatin in tau transgenic Drosophila and mice, and in human AD. Importantly, genetic rescue of tau-induced heterochromatin loss substantially reduced neurodegeneration in Drosophila. We identified oxidative stress and subsequent DNA damage as a mechanistic link between transgenic tau expression and heterochromatin relaxation, and found that heterochromatin loss permits aberrant gene expression in tauopathies. Furthermore, large-scale analyses from human AD brains revealed a widespread transcriptional increase in genes that are heterochromatically silenced in controls. Our results establish heterochromatin loss as a toxic effector of tau-induced neurodegeneration, and identify chromatin structure as a potential therapeutic target in AD
F-Actin Binding Regions on the Androgen Receptor and Huntingtin Increase Aggregation and Alter Aggregate Characteristics
Protein aggregation is associated with neurodegeneration. Polyglutamine expansion diseases such as spinobulbar muscular atrophy and Huntington disease feature proteins that are destabilized by an expanded polyglutamine tract in their N-termini. It has previously been reported that intracellular aggregation of these target proteins, the androgen receptor (AR) and huntingtin (Htt), is modulated by actin-regulatory pathways. Sequences that flank the polyglutamine tract of AR and Htt might influence protein aggregation and toxicity through protein-protein interactions, but this has not been studied in detail. Here we have evaluated an N-terminal 127 amino acid fragment of AR and Htt exon 1. The first 50 amino acids of ARN127 and the first 14 amino acids of Htt exon 1 mediate binding to filamentous actin in vitro. Deletion of these actin-binding regions renders the polyglutamine-expanded forms of ARN127 and Htt exon 1 less aggregation-prone, and increases the SDS-solubility of aggregates that do form. These regions thus appear to alter the aggregation frequency and type of polyglutamine-induced aggregation. These findings highlight the importance of flanking sequences in determining the propensity of unstable proteins to misfold
Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntingtonβs disease model
A polyglutamine expansion in the huntingtin (HTT) gene causes neurodegeneration in Huntingtonβs disease (HD), but the in vivo function of the native protein (Htt) is largely unknown. Numerous biochemical and in vitro studies have suggested a role for Htt in neuronal development, synaptic function and axonal trafficking. To test these models, we generated a null mutant in the putative Drosophila HTT homolog (htt, hereafter referred to asdhtt) and, surprisingly, found that dhtt mutant animals are viable with no obvious developmental defects. Instead, dhtt is required for maintaining the mobility and long-term survival of adult animals, and for modulating axonal terminal complexity in the adult brain. Furthermore, removing endogenous dhtt significantly accelerates the neurodegenerative phenotype associated with a Drosophila model of polyglutamine Htt toxicity (HD-Q93), providing in vivo evidence that disrupting the normal function of Htt might contribute to HD pathogenesis
Nerve Terminal Degeneration Is Independent of Muscle Fiber Genotype in SOD1G93A Mice
Background: Motor neuron degeneration in SOD1 G93A transgenic mice begins at the nerve terminal. Here we examine whether this degeneration depends on expression of mutant SOD1 in muscle fibers. Methodology/Principal Findings: Hindlimb muscles were transplanted between wild-type and SOD1 G93A transgenic mice and the innervation status of neuromuscular junctions (NMJs) was examined after 2 months. The results showed that muscles from SOD1 G93A mice did not induce motor terminal degeneration in wildtype mice and that muscles from wildtype mice did not prevent degeneration in SOD1 G93A transgenic mice. Control studies demonstrated that muscles transplanted from SOD1 G93A mice continued to express mutant SOD1 protein. Experiments on wildtype mice established that the host supplied terminal Schwann cells (TSCs) at the NMJs of transplanted muscles. Conclusions/Significance: These results indicate that expression of the mutant protein in muscle is not needed to cause motor terminal degeneration in SOD1 G93A transgenic mice and that a combination of motor terminals, motor axons and Schwann cells, all of which express mutant protein may be sufficient
A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo
The microtubule binding proteintau is strongly implicated in multiple neurodegenerative disorders, includingfrontotemporal dementia
and parkinsonism linkedto chromosome 17 (FTDP-17), which is caused by mutations intau.In vitro, FTDP-17 mutant versions oftau can
reduce microtubule binding and increase the aggregation of tau, but the mechanism by which these mutations promote disease in vivo is
not clear. Here we take a combined biochemical and in vivo modeling approach to define functional properties of tau driving neurotoxicity in vivo. We express wild-type human tau and five FTDP-17 mutant forms of tau inDrosophila using a site-directed insertion strategy
to ensure equivalent levels of expression. We then analyze multiple markers of neurodegeneration and neurotoxicity in transgenic
animals, including analysis of both males and females. We find that FTDP-17 mutations act to enhance phosphorylation of tau and thus
promote neurotoxicity in an in vivo setting. Further, we demonstrate that phosphorylation-dependent excess stabilization of the actin
cytoskeleton is a key phosphorylation-dependent mediator of the toxicity of wild-type tau and of all the FTDP-17 mutants tested. Finally,
we show that important downstream pathways, including autophagy and the unfolded protein response, are coregulated with neurotoxicity and actin cytoskeletal stabilization in brains of flies expressing wild-type human and various FTDP-17 tau mutants, supporting a
conserved mechanism of neurotoxicity of wild-type tau and FTDP-17 mutant tau in disease pathogenesis.This work wassupported by National Institutes of Health-National Institute of Neurological Disorders and Stroke Grant R01-NS-08339
Decreased Proliferation Kinetics of Mouse Myoblasts Overexpressing FRG1
Although recent publications have linked the molecular events driving facioscapulohumeral muscular dystrophy (FSHD) to expression of the double homeobox transcription factor DUX4, overexpression of FRG1 has been proposed as one alternative causal agent as mice overexpressing FRG1 present with muscular dystrophy. Here, we characterize proliferative defects in two independent myoblast lines overexpressing FRG1. Myoblasts isolated from thigh muscle of FRG1 transgenic mice, an affected dystrophic muscle, exhibit delayed proliferation as measured by decreased clone size, whereas myoblasts isolated from the unaffected diaphragm muscle proliferated normally. To confirm the observation that overexpression of FRG1 could impair myoblast proliferation, we examined C2C12 myoblasts with inducible overexpression of FRG1, finding increased doubling time and G1-phase cells in mass culture after induction of FRG1 and decreased levels of pRb phosphorylation. We propose that depressed myoblast proliferation may contribute to the pathology of mice overexpressing FRG1 and may play a part in FSHD
Characterization of Dysferlin Deficient SJL/J Mice to Assess Preclinical Drug Efficacy: Fasudil Exacerbates Muscle Disease Phenotype
The dysferlin deficient SJL/J mouse strain is commonly used to study dysferlin deficient myopathies. Therefore, we systematically evaluated behavior in relatively young (9β25 weeks) SJL/J mice and compared them to C57BL6 mice to determine which functional end points may be the most effective to use for preclinical studies in the SJL/J strain. SJL/J mice had reduced body weight, lower open field scores, higher creatine kinase levels, and less muscle force than did C57BL6 mice. Power calculations for expected effect sizes indicated that grip strength normalized to body weight and open field activity were the most sensitive indicators of functional status in SJL/J mice. Weight and open field scores of SJL/J mice deteriorated over the course of the study, indicating that progressive myopathy was ongoing even in relatively young (<6 months old) SJL/J mice. To further characterize SJL/J mice within the context of treatment, we assessed the effect of fasudil, a rho-kinase inhibitor, on disease phenotype. Fasudil was evaluated based on previous observations that Rho signaling may be overly activated as part of the inflammatory cascade in SJL/J mice. Fasudil treated SJL/J mice showed increased body weight, but decreased grip strength, horizontal activity, and soleus muscle force, compared to untreated SJL/J controls. Fasudil either improved or had no effect on these outcomes in C57BL6 mice. Fasudil also reduced the number of infiltrating macrophages/monocytes in SJL/J muscle tissue, but had no effect on muscle fiber degeneration/regeneration. These studies provide a basis for standardization of preclinical drug testing trials in the dysferlin deficient SJL/J mice, and identify measures of functional status that are potentially translatable to clinical trial outcomes. In addition, the data provide pharmacological evidence suggesting that activation of rho-kinase, at least in part, may represent a beneficial compensatory response in dysferlin deficient myopathies
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