Catching up -- fly studies related to Huntington's disease, Alzheimer's disease and Parkinson's disease

HD

Besson MT, Alegría K, Garrido-Gerter P, Barros LF, Liévens JC. Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model. PLoS One. 2015 Mar 11;10(3):e0118765. PMID: 25761110; PMCID: PMC4356621.

From the abstract: “... Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD [Huntingtons Disease]. ... Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93). We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. ... To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK) which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. ... Our study confirms the involvement of bioenergetic deficits in HD ...”

Yao Y, Cui X, Al-Ramahi I, Sun X, Li B, Hou J, Difiglia M, Palacino J, Wu ZY, Ma L, Botas J, Lu B. A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity. Elife. 2015 Mar 4;4. doi: 10.7554/eLife.05449. PubMed PMID: 25738228; PubMed Central PMCID: PMC4372774.

From the abstract: “Huntington's disease (HD) ... is mainly caused by cytotoxicity of the mutant huntingtin protein (Htt) with an expanded polyQ stretch. While Htt is ubiquitously expressed, HD is characterized by selective neurodegeneration of the striatum. Here we report a striatal-enriched orphan G protein-coupled receptor(GPCR) Gpr52 as a stabilizer of Htt in vitro and in vivo. ... our discovery reveals modulation of Htt levels by a striatal-enriched GPCR via its GPCR function, providing insights into the selective neurodegeneration and potential treatment strategies.”

AD

Review:

Bouleau S, Tricoire H. Drosophila models of Alzheimer's disease: advances, limits, and perspectives. J Alzheimers Dis. 2015;45(4):1015-38. PMID: 25697708.

Research articles:

Cuesto G, Jordán-Álvarez S, Enriquez-Barreto L, Ferrús A, Morales M, Acebes Á. GSK3β inhibition promotes synaptogenesis in Drosophila and mammalian neurons. PLoS One. 2015 Mar 12;10(3):e0118475. PMID: 25764078; PMCID: PMC4357437.

From the abstract: “... Alzheimer disease's patients exhibit high levels of circulating GSK3β and, consequently, pharmacological strategies based on GSK3β antagonists have been designed. The approach, however, has yielded inconclusive results so far. Here, we carried out a comparative study in Drosophila and rats addressing the role of GSK3β in synaptogenesis. In flies, the genetic inhibition of the shaggy-encoded GSK3β increases the number of synapses, while its upregulation leads to synapse loss. Likewise, in three weeks cultured rat hippocampal neurons, the pharmacological inhibition of GSK3β increases synapse density and Synapsin expression. However, experiments on younger cultures (12 days) yielded an opposite effect, a reduction of synapse density. This unexpected finding seems to unveil an age- and dosage-dependent differential response of mammalian neurons .. a feature that must be considered in the context of ... pharmacological treatments for Alzheimer's disease based on GSK3β antagonists.”

Ping Y, Hahm ET, Waro G, Song Q, Vo-Ba DA, Licursi A, Bao H, Ganoe L, Finch K, Tsunoda S. Linking aβ42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model. PLoS Genet. 2015 Mar 16;11(3):e1005025. PMID: 25774758; PMCID: PMC4361604.

From the abstract: “Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly. β-amyloid (Aβ) accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. ... Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. ... We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.”

PD

Review:

Vanhauwaert R, Verstreken P. Flies with Parkinson's disease. Exp Neurol. 2015 Feb 20. pii: S0014-4886(15)00043-6. PMID: 25708988.

Research articles:

van der Merwe C, Jalali Sefid Dashti Z, Christoffels A, Loos B, Bardien S. Evidence for a common biological pathway linking three Parkinson's disease-causing genes: parkin, PINK1 and DJ-1. Eur J Neurosci. 2015 May;41(9):1113-25. PMID: 25761903.

From the abstract: “Parkinson's disease (PD) is characterised by the loss of dopaminergic neurons in the midbrain. Autosomal recessive, early-onset cases of PD are predominantly caused by mutations in the parkin, PINK1 and DJ-1 genes. Animal and cellular models have verified a direct link between parkin and PINK1, whereby PINK1 phosphorylates and activates parkin at the outer mitochondrial membrane, resulting in removal of dysfunctional mitochondria via mitophagy. Despite the overwhelming evidence for this interaction, few studies have been able to identify a link for DJ-1 with parkin or PINK1. The aim of this review is to summarise the functions of these three proteins, and to analyse the existing evidence for direct and indirect interactions between them. ...”

Zhu M, Li X, Tian X, Wu C. Mask loss-of-function rescues mitochondrial impairment and muscle degeneration of Drosophila pink1 and parkin mutants. Hum Mol Genet. 2015 Jun 1;24(11):3272-85. doi: 10.1093/hmg/ddv081. Epub 2015 Mar 5. PubMed PMID: 25743185; PubMed Central PMCID: PMC4424960.

From the abstract: “PTEN-induced kinase 1 (Pink1) and ubiquitin E3 ligase Parkin function in a linear pathway to maintain healthy mitochondria ... Mutations in the two enzymes cause the familial form of Parkinson's disease (PD) in humans, as well as accumulation of defective mitochondria and cellular degeneration in flies. Here, we show that loss of function of a scaffolding protein Mask, also known as ANKHD1 (Ankyrin repeats and KH domain containing protein 1) in humans, rescues the behavioral, anatomical and cellular defects caused by pink1 or parkin mutations in a cell-autonomous manner. ... Together, our data strongly suggest that Mask/ANKHD1 activity can be inhibited in a tissue- and timely-controlled fashion to restore mitochondrial integrity under PD-linked pathological conditions.”