Berson A, Sartoris A, Nativio R, Van Deerlin V, Toledo JB, Porta S, Liu S, Chung CY, Garcia BA, Lee VM, Trojanowski JQ, Johnson FB, Berger SL, Bonini NM. TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr Biol. 2017 Nov 9. pii: S0960-9822(17)31327-1. PMID: 29153328.
The abstract: "Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD)."
Tuesday, November 21, 2017
Monday, November 13, 2017
Review discusses use of Drosophila in studies of neurological diseases
Şentürk M, Bellen HJ. Genetic strategies to tackle neurological diseases in fruit flies. Curr Opin Neurobiol. 2017 Nov 8;50:24-32. PMID: 29128849.
The abstract: "Drosophila melanogaster is a genetic model organism that has contributed to the discovery of numerous genes whose human homologues are associated with diseases. The development of sophisticated genetic tools to manipulate its genome accelerates the discovery of the genetic basis of undiagnosed human diseases and the elucidation of molecular pathogenic events of known and novel diseases. Here, we discuss various approaches used in flies to assess the function of the fly homologues of disease-associated genes. We highlight how systematic and combinatorial approaches based on recently established methods provide us with integrated tool sets that can be applied to the study of neurodevelopmental and neurodegenerative disorders."
The abstract: "Drosophila melanogaster is a genetic model organism that has contributed to the discovery of numerous genes whose human homologues are associated with diseases. The development of sophisticated genetic tools to manipulate its genome accelerates the discovery of the genetic basis of undiagnosed human diseases and the elucidation of molecular pathogenic events of known and novel diseases. Here, we discuss various approaches used in flies to assess the function of the fly homologues of disease-associated genes. We highlight how systematic and combinatorial approaches based on recently established methods provide us with integrated tool sets that can be applied to the study of neurodevelopmental and neurodegenerative disorders."
Wednesday, November 8, 2017
Drosophila mode of Alzheimer's disease explores relevance of glial engulfment receptor Draper
Ray A, Speese SD, Logan MA. Glial Draper rescues Aβ toxicity in a Drosophila model of Alzheimer's Disease. J Neurosci. 2017 Nov 6. pii: 0862-17. PMID: 29109235.
From the abstract: "Pathological hallmarks of Alzheimer's disease (AD) include amyloid-beta (Aβ) plaques, neurofibrillary tangles, and reactive gliosis. Glial cells offer protection against AD by engulfing extracellular Aβ peptides, but the repertoire of molecules required for glial recognition and destruction of Aβ are still unclear. Here, we show that the highly conserved glial engulfment receptor Draper/MEGF10 provides neuroprotection in an AD model of Drosophila (both sexes). ... Here we show that the glial engulfment receptor Draper is protective in a Drosophila model of AD, reducing levels of amyloid beta (Aβ) peptides, reversing locomotor defects, and extending lifespan. We further show that protein degradation pathways are induced downstream of Draper in AD model flies, supporting a model in which glia engulf and destroy Aβ peptides to reduce amyloid-associated toxicity."
From the abstract: "Pathological hallmarks of Alzheimer's disease (AD) include amyloid-beta (Aβ) plaques, neurofibrillary tangles, and reactive gliosis. Glial cells offer protection against AD by engulfing extracellular Aβ peptides, but the repertoire of molecules required for glial recognition and destruction of Aβ are still unclear. Here, we show that the highly conserved glial engulfment receptor Draper/MEGF10 provides neuroprotection in an AD model of Drosophila (both sexes). ... Here we show that the glial engulfment receptor Draper is protective in a Drosophila model of AD, reducing levels of amyloid beta (Aβ) peptides, reversing locomotor defects, and extending lifespan. We further show that protein degradation pathways are induced downstream of Draper in AD model flies, supporting a model in which glia engulf and destroy Aβ peptides to reduce amyloid-associated toxicity."
Fly studies contribute to understanding of Brown-Vialetto-Van Laere syndrome with implications for a possible treatment strategy
Manole A, Jaunmuktane Z, Hargreaves I, Ludtmann MHR, Salpietro V, Bello OD, Pope S, Pandraud A, Horga A, Scalco RS, Li A, Ashokkumar B, Lourenço CM, Heales S, Horvath R, Chinnery PF, Toro C, Singleton AB, Jacques TS, Abramov AY, Muntoni F, Hanna MG, Reilly MM, Revesz T, Kullmann DM, Jepson JEC, Houlden H. Clinical, pathological and functional characterization of riboflavin-responsive neuropathy. Brain. 2017 Nov 1;140(11):2820-2837. PMID: 29053833.
From the abstract: "Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. ... By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome ... global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity ... Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology ... Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy."
From the abstract: "Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. ... By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome ... global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity ... Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology ... Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy."
Fly research helps inform understanding of signal pathway roles in Schimke immuno-osseous dysplasia
Morimoto M, Myung C, Beirnes K, Choi K, Asakura Y, Bokenkamp A, Bonneau D, Brugnara M, Charrow J, Colin E, Davis A, Deschenes G, Gentile M, Giordano M, Gormley AK, Govender R, Joseph M, Keller K, Lerut E, Levtchenko E, Massella L, Mayfield C, Najafian B, Parham D, Spranger J, Stenzel P, Yis U, Yu Z, Zonana J, Hendson G, Boerkoel CF. Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia? Orphanet J Rare Dis. 2016 Nov 5;11(1):149. PMID: 27816064; PMCID: PMC5097426.
From the abstract: "Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. ... we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. ... We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients."
From the abstract: "Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. ... we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. ... We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients."
Monday, November 6, 2017
Drosophila studies inform understanding of cellular mechanisms underlying Snyder-Robinson syndrome
Li C, Brazill JM, Liu S, Bello C, Zhu Y, Morimoto M, Cascio L, Pauly R, Diaz-Perez Z, Malicdan MCV, Wang H, Boccuto L, Schwartz CE, Gahl WA, Boerkoel CF, Zhai RG. Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome. Nat Commun. 2017 Nov 2;8(1):1257. PMID: 29097652.
From the abstract: "... Loss-of-function mutations in spermine synthase (SMS), a polyamine biosynthesis enzyme, cause Snyder-Robinson syndrome (SRS), an X-linked intellectual disability syndrome ... Here we show that loss of dSms in Drosophila recapitulates the pathological polyamine imbalance of SRS and causes survival defects and synaptic degeneration. ... Our findings uncover some of the mechanisms underlying the pathological consequences of abnormal polyamine metabolism in the nervous system and may provide potential therapeutic targets for treating SRS and other polyamine-associated neurological disorders."
From the abstract: "... Loss-of-function mutations in spermine synthase (SMS), a polyamine biosynthesis enzyme, cause Snyder-Robinson syndrome (SRS), an X-linked intellectual disability syndrome ... Here we show that loss of dSms in Drosophila recapitulates the pathological polyamine imbalance of SRS and causes survival defects and synaptic degeneration. ... Our findings uncover some of the mechanisms underlying the pathological consequences of abnormal polyamine metabolism in the nervous system and may provide potential therapeutic targets for treating SRS and other polyamine-associated neurological disorders."
Subscribe to:
Posts (Atom)