Wednesday, December 4, 2019

New fly models of Spinocerebellar ataxia type 31

Ishikawa K, Nagai Y. Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31). Neurotherapeutics. 2019 Nov 21. PubMed PMID: 31755042.

From the abstract: "Spinocerebellar ataxia type 31 (SCA31) is one of the autosomal-dominant neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom. This disease is caused by a 2.5- to 3.8-kb-long complex pentanucleotide repeat containing (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n in an intron of the gene called BEAN1 (brain expressed, associated with Nedd4). ... To dissect the pathogenesis of (UGGAA)n in SCA31, we generated transgenic fly models of SCA31 by overexpressing SCA31 complex pentanucleotide repeats in Drosophila. We found that the toxicity of (UGGAA)n is length- and expression level-dependent, and it was dampened by co-expressing TDP-43, FUS, and hnRNP A2/B1. ..."

Cross-species studies explores mechanisms underlying premature again in Werner syndrome

Fang EF, Hou Y, Lautrup S, Jensen MB, Yang B, SenGupta T, Caponio D, Khezri R, Demarest TG, Aman Y, Figueroa D, Morevati M, Lee HJ, Kato H, Kassahun H, Lee JH, Filippelli D, Okur MN, Mangerich A, Croteau DL, Maezawa Y, Lyssiotis CA, Tao J, Yokote K, Rusten TE, Mattson MP, Jasper H, Nilsen H, Bohr VA. NAD(+) augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat Commun. 2019 Nov 21;10(1):5284. PubMed PMID: 31754102; PubMed Central PMCID: PMC6872719.

Abstract: "Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes ... Here we report impaired mitophagy and depletion of ... At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes."

Drosophila studies point to potential relevance of voltage-gated sodium channels in cell proliferation and cancer

Piggott BJ, Peters CJ, He Y, Huang X, Younger S, Jan LY, Jan YN. Paralytic, the Drosophila voltage-gated sodium channel, regulates proliferation of neural progenitors. Genes Dev. 2019 Dec 1;33(23-24):1739-1750. PubMed PMID: 31753914.

From the abstract: "... voltage-gated sodium channels (VGSC) that are crucial for neuronal excitability are also found in progenitors and up-regulated in cancer. Here, we identify a role for VGSC in proliferation of Drosophila neuroblast (NB) lineages within the central nervous system. Loss of paralytic (para), the sole gene that encodes Drosophila VGSC, reduces neuroblast progeny cell number. ... Our data suggests that loss of Para induces apoptosis in this population, whereas overexpression leads to an increase in INPs and overall neuroblast progeny cell numbers. These effects are cell autonomous and depend on Para channel activity. Reduction of Para expression not only affects normal NB development, but also strongly suppresses brain tumor mass, implicating a role for Para in cancer progression. To our knowledge, our studies are the first to identify a role for VGSC in neural progenitor proliferation. Elucidating the contribution of VGSC in proliferation will advance our understanding of bioelectric signaling within development and disease states."

Studies in Drosophila point to potential therapeutic approach for treatment of Parkinson's Disease based on modulation of kynurenine metabolism

Cunningham PC, Waldeck K, Ganetzky B, Babcock DT. Neurodegeneration and locomotor dysfunction in Drosophila scarlet mutants. J Cell Sci. 2018 Sep 17;131(18). pii: jcs216697. doi: 10.1242/jcs.216697. PubMed PMID: 30154211; PubMed Central PMCID: PMC6176922.

From the abstract: "Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons, resulting in progressive locomotor dysfunction. Identification of genes required for the maintenance of these neurons should help to identify potential therapeutic targets. ... Here, we show that Drosophila melanogaster scarlet mutants exhibit an age-dependent progressive loss of dopaminergic neurons, along with subsequent locomotor defects and a shortened lifespan. ... we show that expression of wild-type Scarlet is neuroprotective in a model of PD, suggesting that manipulating kynurenine metabolism may be a potential therapeutic option in treating PD."

Flies used to explore potential health impacts of a food additive

Jovanović B, Jovanović N, Cvetković VJ, Matić S, Stanić S, Whitley EM, Mitrović TL. The effects of a human food additive, titanium dioxide nanoparticles E171, on Drosophila melanogaster - a 20 generation dietary exposure experiment. Sci Rep. 2018 Dec 18;8(1):17922. PubMed PMID: 30560898; PubMed Central PMCID: PMC6298969.

Abstract: "In this study, fruit flies (Drosophila melanogaster) were exposed to an estimated daily human E171 consumption concentration for 20 generations. Exposure to E171 resulted in: a change in normal developmental and reproductive dynamics, reduced fecundity after repetitive breeding, increased genotoxicity, the appearance of aberrant phenotypes and morphologic changes to the adult fat body. Marks of adaptive evolution and directional selection were also exhibited. The larval stages were at a higher risk of sustaining damage from E171 as they had a slower elimination rate of TiO2 compared to the adults. This is particularly worrisome, since among the human population, children tend to consume higher daily concentrations of E171 than do adults. The genotoxic effect of E171 was statistically higher in each subsequent generation compared to the previous one. Aberrant phenotypes were likely caused by developmental defects induced by E171, and were not mutations, since the phenotypic features were not transferred to any progeny even after 5 generations of consecutive crossbreeding. Therefore, exposure to E171 during the early developmental period carries a higher risk of toxicity. The fact that the daily human consumption concentration of E171 interferes with and influences fruit fly physiological, ontogenetic, genotoxic, and adaptive processes certainly raises safety concerns."

Fly studies help provide insights into molecular mechanisms related to Charcot-Marie-Tooth and related disorders

Suda K, Muraoka Y, Ortega-Yáñez A, Yoshida H, Kizu F, Hochin T, Kimura H, Yamaguchi M. Reduction of Rpd3 suppresses defects in locomotive ability and neuronal morphology induced by the knockdown of Drosophila SLC25A46 via an epigenetic pathway. Exp Cell Res. 2019 Dec 15;385(2):111673. PubMed PMID: 31614134.

Abstract: "Mitochondrial dysfunction causes various diseases. Mutations in the SLC25A46 gene have been identified in mitochondrial diseases that are sometimes classified as Charcot-Marie-Tooth disease type 2, optic atrophy, and Leigh syndrome. A homolog of SLC25A46 was identified in Drosophila and designated as dSLC25A46 (CG5755). We previously established mitochondrial disease model targeting of dSLC25A46, which causes locomotive dysfunction and morphological defects at neuromuscular junctions, such as reduced synaptic branch lengths and decreased numbers of boutons. The diverse symptoms of mitochondrial diseases carrying mutations in SLC25A46 may be associated with the dysregulation of some epigenetic regulators. To investigate the involvement of epigenetic regulators in mitochondrial diseases, we examined candidate epigenetic regulators that interact with human SLC25A46 by searching Gene Expression Omnibus (GEO). We discovered that HDAC1 binds to several SLC25A46 genomic regions in human cultured CD4 (+) cells, and attempted to prove this in an in vivo Drosophila model. By demonstrating that Rpd3, Drosophila HDAC1, regulates the histone H4K8 acetylation state in dSLC25A46 genomic regions, we confirmed that Rpd3 is a novel epigenetic regulator modifying the phenotypes observed with the mitochondrial disease model targeting of dSLC25A46. The functional reduction of Rpd3 rescued the deficient locomotive ability and aberrant morphology of motoneurons at presynaptic terminals induced by the dSLC25A46 knockdown. The present results suggest that the inhibition of HDAC1 suppresses the pathogenic processes that lead to the degeneration of motoneurons in mitochondrial diseases."

Cross-species study helps provide insight on the human gene IQSEC1, variants in which are associated with developmental disease

Ansar M, Chung HL, Al-Otaibi A, Elagabani MN, Ravenscroft TA, Paracha SA, Scholz R, Abdel Magid T, Sarwar MT, Shah SF, Qaisar AA, Makrythanasis P, Marcogliese PC, Kamsteeg EJ, Falconnet E, Ranza E, Santoni FA, Aldhalaan H, Al-Asmari A, Faqeih EA, Ahmed J, Kornau HC, Bellen HJ, Antonarakis SE. Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature. Am J Hum Genet. 2019 Nov 7;105(5):907-920. PubMed PMID: 31607425; PubMed Central PMCID: PMC6848997.

From the abstract: "We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). ... IQSEC1-3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis."