Friday, October 30, 2015

New fly model of Parkinson's disease--alteration of the fly PGC-1alpha ortholog, spargel (srl)

Merzetti EM, Staveley BE. spargel, the PGC-1α homologue, in models of Parkinson disease in Drosophila melanogaster. Free online in BMC Neurosci. 2015 Oct 26;16(1):70. PMID: 26502946; PMCID: PMC4623274.

From the abstract: "... Directed expression of [RNAi against the Drosophila PGC-1alpha ortholog spargel (srl)] in the D. melanogaster eye causes abnormal ommatidia and bristle formation ... Ddc-Gal4 mediated tissue specific expression of srl transgene constructs in D. melanogaster DA neurons causes altered lifespan and climbing ability. Expression of a srl-RNAi causes an increase in mean lifespan but a decrease in overall loco-motor ability while induced expression of srl-EY causes a severe decrease in mean lifespan and a decrease in loco-motor ability ... The reduced lifespan and climbing ability associated with a tissue specific expression of srl in DA neurons provides a new model of PD in D. melanogaster ..."

Sleep-deprived and feeling it: new use of fly as a model of sleep deprivation-related seizures

Lucey BP, Leahy A, Rosas R, Shaw PJ. A new model to study sleep deprivation-induced seizure. Free online at Sleep. 2015 May 1;38(5):777-85. PMID: 25515102.

Friday, October 23, 2015

Report of new insights into mitochondrial retrograde signaling and its impact in Leigh syndrome and Parkinson's and other neurodegenerative diseases

Cagin U, Duncan OF, Gatt AP, Dionne MS, Sweeney ST, Bateman JM. Mitochondrial retrograde signaling regulates neuronal function. Proc Natl Acad Sci U S A. 2015 Oct 21. pii: 201505036. PMID: 26489648.

From the abstract: "Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer's and Parkinson's. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. ... We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson's disease. ..."

Wednesday, October 7, 2015

Launch of FlyBook includes review on fly models of neurodegenerative diseases

Launch of the FlyBook resource at the journal Genetics includes this disease-relevant review:

Leeanne McGurk, Amit Berson and Nancy M. Bonini (2015) Drosophila as an In Vivo Model for Human Neurodegenerative Disease. Genetics.

Tuesday, October 6, 2015

Results of two studies suggest disruption of RNA export from nucleus is a mechansim of neurodegenation in ALS and frontodemporal dementia

Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):129-33. PMID: 26308899.

From the abstract: "The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. ... To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. ... These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration. "

Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. PMID: 26308891.

From the abstract: "... A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention. "

See also comment in: Fox BW, Tibbetts RS. Neurodegeneration: Problems at the nuclear pore. Nature. 2015 Sep 3;525(7567):36-7. PMID: 26308896.

Clinical trial to follow study of GABAAergic system in Fragile X syndrome using mice and flies

Braat S, Kooy RF. Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials. Neuropharmacology. 2015 Jan;88:48-54. PMID: 25016041.

From the abstract: "An increasing number of studies implicate the GABAAergic system in the pathophysiology of the fragile X syndrome, a frequent cause of intellectual disability and autism. Animal models have proven invaluable ... Aberrations compatible with those described in the mouse model were detected in dfmr1 deficient Drosophila melanogaster, a validated fly model for the fragile X syndrome. Treatment with drugs that ameliorate the GABAAergic deficiency in both animal models have demonstrated that the GABAA receptor is a promising target for the treatment of fragile X patients. Based on these preclinical studies, clinical trials in patients have been initiated."

Monday, October 5, 2015

Funny-named "ether-a-go-go" has potentially serious impact in development of brain tumor treatments

Huang X, He Y, Dubuc AM, Hashizume R, Zhang W, Reimand J, Yang H, Wang TA, Stehbens SJ, Younger S, Barshow S, Zhu S, Cooper MK, Peacock J, Ramaswamy V, Garzia L, Wu X, Remke M, Forester CM, Kim CC, Weiss WA, James CD, Shuman MA, Bader GD, Mueller S, Taylor MD, Jan YN, Jan LY. EAG2 potassium channel with evolutionarily conserved function as a brain tumor target. Nat Neurosci. 2015 Sep;18(9):1236-46. PMID: 26258683.

From the abstract: "... We found that the EAG2 (Ether-a-go-go 2) potassium channel has an evolutionarily conserved function for promoting brain tumor growth and metastasis ... We identified the FDA-approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings illustrate the potential of targeting ion channels in cancer treatment."

A 'how-to' review--small molecule screens with fly models of neurological disorders

Poidevin M, Zhang F, Jin P. Small-molecule screening using Drosophila models of human neurological disorders. Methods Mol Biol. 2015;1263:127-38. PMID: 25618341.

From the abstract:
“… Drosophila has emerged as a premiere model system for the study of human neurodegenerative diseases, due to the realization that flies and humans share many structurally and functionally related gene families. ... Here, we describe how to utilize the existing fruit fly models of human neurological disorders to identify small-molecule leads that could potentially be further developed for therapeutic use.”