Fly model of Tauopathies contributes to study related to pTau interaction with Hsp27

Elife. 2022 Sep 1;11:e79898. doi: 10.7554/eLife.79898.

Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology.

Zhang S, Zhu Y, Lu J, Liu Z, Lobato AG, Zeng W, Liu J, Qiang J, Zeng S, Zhang Y, Liu C, Liu J, He
Z, Zhai RG, Li D

Abstract:

Amyloid aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles is closely associated with Alzheimer's disease (AD). Several molecular chaperones have been reported to bind Tau and impede its pathological aggregation. Recent findings of elevated levels of Hsp27 in the brains of patients with AD suggested its important role in pTau pathology. However, the molecular mechanism of Hsp27 in pTau aggregation remains poorly understood. Here, we show that Hsp27 partially co-localizes with pTau tangles in the brains of patients with AD. Notably, phosphorylation of Tau by microtubule affinity regulating kinase 2 (MARK2), dramatically enhances the binding affinity of Hsp27 to Tau. Moreover, Hsp27 efficiently prevents pTau fibrillation in vitro and mitigates neuropathology of pTau aggregation in a Drosophila tauopathy model. Further mechanistic study reveals that Hsp27 employs its N-terminal domain to directly interact with multiple phosphorylation sites of pTau for specific binding. Our work provides the structural basis for the specific recognition of Hsp27 to pathogenic pTau, and highlights the important role of Hsp27 in preventing abnormal aggregation and pathology of pTau in AD.

DOI: 10.7554/eLife.79898
PMID: 36048712

Drosophila study related to aging and age-related disorders

Proc Natl Acad Sci U S A. 2021 Oct 5;118(40):e2110387118.

A genetic model of methionine restriction extends Drosophila health- and
lifespan.

Parkhitko AA, Wang L, Filine E, Jouandin P, Leshchiner D, Binari R, Asara JM, Rabinowitz JD, Perrimon N

Loss of metabolic homeostasis is a hallmark of aging and is characterized by dramatic metabolic reprogramming. To analyze how the fate of labeled methionine is altered during aging, we applied 13C5-Methionine labeling to Drosophila and demonstrated significant changes in the activity of different branches of the methionine metabolism as flies age. We further tested whether targeted degradation of methionine metabolism components would "reset" methionine metabolism flux and extend the fly lifespan. Specifically, we created transgenic flies with inducible expression of Methioninase, a bacterial enzyme capable of degrading methionine and revealed methionine requirements for normal maintenance of lifespan. We also demonstrated that microbiota-derived methionine is an alternative and important source in addition to food-derived methionine. In this genetic model of methionine restriction (MetR), we also demonstrate that either whole-body or tissue-specific Methioninase expression can dramatically extend Drosophila health- and lifespan and exerts physiological effects associated with MetR. Interestingly, while previous dietary MetR extended lifespan in flies only in low amino acid conditions, MetR from Methioninase expression extends lifespan independently of amino acid levels in the food. Finally, because impairment of the methionine metabolism has been previously associated with the development of Alzheimer's disease, we compared methionine metabolism reprogramming between aging flies and a Drosophila model relevant to Alzheimer's disease, and found that overexpression of human Tau caused methionine metabolism flux reprogramming similar to the changes found in aged flies. Altogether, our study highlights Methioninase as a potential agent for health- and lifespan extension.

DOI: 10.1073/pnas.2110387118
PMID: 34588310

Several new studies and a review related to Alzheimer's disease and other neurodegenerative and age-related disorders

Goldberg J, Currais A, Prior M, Fischer W, Chiruta C, Ratliff E, Daugherty D, Dargusch R, Finley K, Esparza-Moltó PB, Cuezva JM, Maher P, Petrascheck M, Schubert D. The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging Cell. 2018 Apr;17(2). PubMed PMID: 29316249; PubMed Central PMCID: PMC5847861.

Ojelade SA, Lee TV, Giagtzoglou N, Yu L, Ugur B, Li Y, Duraine L, Zuo Z, Petyuk V, De Jager PL, Bennett DA, Arenkiel BR, Bellen HJ, Shulman JM. cindr, the Drosophila Homolog of the CD2AP Alzheimer's Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis. Cell Rep. 2019 Aug 13;28(7):1799-1813.e5. PubMed PMID: 31412248; PubMed Central PMCID:
PMC6703184.

Yang L, Cao Y, Zhao J, Fang Y, Liu N, Zhang Y. Multidimensional proteomics identifies declines in protein homeostasis and mitochondria as early signals for normal aging and age-associated disease in Drosophila. Mol Cell Proteomics. 2019 Aug 21. pii: mcp.RA119.001621. PubMed PMID: 31434710.

Park SY, Seo J, Chun YS. Targeted Downregulation of kdm4a Ameliorates Tau-engendered Defects in Drosophila melanogaster. J Korean Med Sci. 2019 Aug 26;34(33):e225. doi: 10.3346/jkms.2019.34.e225. PubMed PMID: 31436053; PubMed Central PMCID: PMC6706347.

Sun M, Zhao Y, Han M, Zhang B, Zhang X, Zhang Q, Lim NK, Wang WA, Huang FD. TTC7 and Hyccin Regulate Neuronal Aβ42 Accumulation and its Associated Neural Deficits in Aβ42-Expressing Drosophila. J Alzheimers Dis. 2018;65(3):1001-1010. PubMed PMID: 30103315.

Passarella D, Goedert M. Beta-sheet assembly of Tau and neurodegeneration in Drosophila melanogaster. Neurobiol Aging. 2018 Dec;72:98-105. PubMed PMID: 30240946;
PubMed Central PMCID: PMC6327151.

Gusareva ES, Twizere JC, Sleegers K, Dourlen P, Abisambra JF, Meier S, Cloyd R, Weiss B, Dermaut B, Bessonov K, et al. Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease. Neurobiol Aging. 2018 Dec;72:188.e3-188.e12. PubMed PMID: 30201328.

Jantrapirom S, Lo Piccolo L, Yamaguchi M. Non-Proteasomal UbL-UbA Family of Proteins in Neurodegeneration. Int J Mol Sci. 2019 Apr 17;20(8). pii: E1893. Review. PubMed PMID: 30999567; PubMed Central PMCID: PMC6514573.

Bajracharya R, Youngson NA, Ballard JWO. Dietary Macronutrient Management to Treat Mitochondrial Dysfunction in Parkinson's Disease. Int J Mol Sci. 2019 Apr 15;20(8). pii: E1850. doi: 10.3390/ijms20081850. Review. PubMed PMID: 30991634; PubMed Central PMCID: PMC6514887.

Fly model of FTD used to identify compound reported to reduce toxic phosphorylated tau

Shim KH, Kim SH, Hur J, Kim DH, Demirev AV, Yoon SY. Small-molecule drug screening identifies drug Ro 31-8220 that reduces toxic phosphorylated tau in Drosophila melanogaster. Neurobiol Dis. 2019 Jun 21:104519. doi: 10.1016/j.nbd.2019.104519. PMID: 31233882.

Abstract: "The intraneuronal aggregates of hyperphosphorylated and misfolded tau (neurofibrillary tangles, NFTs) cause a stereotypical spatiotemporal Alzheimer's disease (AD) progression that correlates with the severity of the associated cognitive decline. Kinase activity contributes to the balance between neuron survival and cell death. Hyperactivation of kinases including the conventional protein kinase C (PKC) is a defective molecular event accompanying associative memory loss, tau phosphorylation, and progression of AD or related neurodegenerative diseases. Here, we investigated the ability of small therapeutic compounds (a custom library) to improve tau-induced rough-eye phenotype in a Drosophila melanogaster model of frontotemporal dementia. We also assessed the tau phosphorylation in vivo and selected hit compounds. Among the potential hits, we investigated Ro 31-8220, described earlier as a potent PKCα inhibitor. Ro 31-8220 robustly improved the rough-eye phenotype, reduced phosphorylated tau species in vitro and in vivo, reversed tau-induced memory impairment, and improved the fly motor functions. In a human neuroblastoma cell line, Ro 31-8220 reduced the PKC activity and the tau phosphorylation pattern, but we also have to acknowledge the compound's wide range of biological activity. Nevertheless, Ro 31-8220 is a novel therapeutic mitigator of tau-induced neurotoxocity."

Methods report--using the fly eye to study Tau toxicity

Dourlen P. Identification of Tau Toxicity Modifiers in the Drosophila Eye. Methods Mol Biol. 2017;1523:375-389 PMID: 27975266.

The abstract: "Drosophila is a powerful model to study human diseases thanks to its genetic tools and ease of screening. Human genes can be expressed in targeted organs and their toxicity assessed on easily scorable external phenotypes that can be used as readout to perform genetic screen of toxicity modifiers. In this chapter, I describe how to express human Tau protein in the Drosophila eye, assess protein expression by western blot, assess Tau toxicity by quantifying the size of the Tau-induced rough eye, and perform a genetic screen of modifiers of Tau toxicity in the Drosophila eye."

Results of a study in Drosophila suggest the possible relevance of neuronal aneuploidy to Tau-associated neurodegeneration

Malmanche N, Dourlen P, Gistelinck M, Demiautte F, Link N, Dupont C, Vanden Broeck L, Werkmeister E, Amouyel P, Bongiovanni A, Bauderlique H, Moechars D, Royou A, Bellen HJ, Lafont F, Callaerts P, Lambert JC, Dermaut B. Developmental Expression of 4-Repeat-Tau Induces Neuronal Aneuploidy in Drosophila Tauopathy Models. Sci Rep. 2017 Jan 23;7:40764. PMID: 28112163.

From the abstract: "Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. ... Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. ... we found a high level of aneuploidy in post-mitotic differentiated tissue. ... our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development."

Fly wing disc tissue used to study neurodegenerative disease-related cellular activities

Bougé AL, Parmentier ML. Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death. Dis Model Mech. 2016 Mar;9(3):307-19. PMID: 26822478; PMCID: PMC4833329.

From the abstract: "In neurodegenerative diseases such as Alzheimer's disease (AD), cell cycle defects and associated aneuploidy have been described. However, the importance of these defects in the physiopathology of AD and the underlying mechanistic processes are largely unknown... Here, we studied the effect of an excess of human Tau (hTau) protein on cell mitosis in vivo. Using the Drosophila developing wing disc epithelium as a model, we show that an excess of hTau induces a mitotic arrest, with the presence of monopolar spindles. This mitotic defect leads to aneuploidy and apoptotic cell death. We studied the mechanism of action of hTau and found that the MT-binding domain of hTau is responsible for these defects. ... We finally show that this deleterious effect of hTau is also found in other Drosophila cell types (neuroblasts) and tissues (the developing eye disc), as well as in human HeLa cells. By demonstrating that MT-bound Tau inhibits the Eg5 kinesin and cell mitosis, our work provides a new framework to consider the role of Tau in neurodegenerative diseases."

Review of Drosophila and other invertebrate models of Tauopathies

Hannan SB, Dräger NM, Rasse TM, Voigt A, Jahn TR. Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models. J Neurochem. 2016 Apr;137(1):12-25. PMID: 26756400.

From the abstract: "Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) ... An important discovery came with the demonstration that over-expression of human tau in Drosophila leads to premature mortality and neuronal dysfunction including neurodegeneration, recapitulating some key neuropathological features of the human disease. ... We discuss the utility and application of invertebrate models in elucidating the cellular and molecular functions of novel and uncharacterized disease modifiers identified in large-scale screens as well as for investigating the function of genes identified as risk factors in genome-wide association studies from human patients in the post-genomic era. ..."

More catching up -- fly models helping to reveal new insights into neurodegenertive diseases

Parkinson's Disease

Reviews

Gaki GS, Papavassiliou AG. Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson's disease. Neuromolecular Med. 2014 Jun;16(2):217-30. PMID: 24522549.

Deng H, Yuan L. Genetic variants and animal models in SNCA and Parkinson disease. Ageing Res Rev. 2014 May;15:161-76. PMID: 24768741.

Research reports

Büttner S, Broeskamp F, Sommer C, Markaki M, Habernig L, Alavian-Ghavanini A, Carmona-Gutierrez D, Eisenberg T, Michael E, Kroemer G, Tavernarakis N, Sigrist SJ, Madeo F. Spermidine protects against α-synuclein neurotoxicity. Cell Cycle. 2014;13(24):3903-8. PMID: 25483063.

Siddique YH, Naz F, Jyoti S, Fatima A, Khanam S, Rahul, Ali F, Mujtaba SF, Faisal M. Effect of Centella asiatica Leaf Extract on the Dietary Supplementation in Transgenic Drosophila Model of Parkinson's Disease. Parkinsons Dis. 2014;2014:262058. PMID: 25538856; PMCID: PMC4265550.

Roy B, Jackson GR. Interactions between Tau and α-synuclein augment neurotoxicity in a Drosophila model of Parkinson's disease. Hum Mol Genet. 2014 Jun 1;23(11):3008-23. PMID:
24430504; PMCID: PMC4014195. From the abstract: "Clinical and pathological studies have suggested considerable overlap between tauopathies and synucleinopathies. Several genome-wide association studies have identified alpha-Synuclein (SNCA) and Tau (MAPT) polymorphisms as common risk factors for sporadic Parkinson's disease (PD). However, the mechanisms by which subtle variations in the expression of wild-type SNCA and MAPT influence risk for PD and the underlying cellular events that effect neurotoxicity remain unclear. To examine causes of neurotoxicity associated with the α-Syn/Tau interaction, we used the fruit fly as a model. ... "

Angeles DC, Ho P, Chua LL, Wang C, Yap YW, Ng C, Zhou Zd, Lim KL, Wszolek ZK, Wang HY, Tan EK. Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila. Hum Mol Genet. 2014 Jun 15;23(12):3157-65. PMID: 24459295; PMCID: PMC4030771.

Alzheimer's Disease and Tauopathies

Wacker J, Rönicke R, Westermann M, Wulff M, Reymann KG, Dobson CM, Horn U, Crowther DC, Luheshi LM, Fändrich M. Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. Acta Neuropathol Commun. 2014 Apr 11;2:43. PMID: 24725347; PMCID: PMC4029271.

Papanikolopoulou K, Skoulakis EM. Temporally distinct phosphorylations differentiate Tau-dependent learning deficits and premature mortality in Drosophila. Hum Mol Genet. 2015 Apr 1;24(7):2065-77. doi: 10.1093/hmg/ddu726. PMID: 25524708.

Santa-Maria I, Alaniz ME, Renwick N, Cela C, Fulga TA, Van Vactor D, Tuschl T, Clark LN, Shelanski ML, McCabe BD, Crary JF. Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. J Clin Invest. 2015 Feb;125(2):681-6. PubMed PMID: 25574843; PMCID: PMC4319412.

Huntington's Disease

Maheshwari M, Bhutani S, Das A, Mukherjee R, Sharma A, Kino Y, Nukina N, Jana NR. Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington's disease. Hum Mol Genet. 2014 May 15;23(10):2737-51. PMID: 24381308.

Lu XH, Mattis VB, Wang N, Al-Ramahi I, van den Berg N, Fratantoni SA, Waldvogel H, Greiner E, Osmand A, Elzein K, Xiao J, Dijkstra S, de Pril R, Vinters HV, Faull R, Signer E, Kwak S, Marugan JJ, Botas J, Fischer DF, Svendsen CN, Munoz-Sanjuan I, Yang XW. Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington's disease. Sci Transl Med. 2014 Dec 24;6(268):268ra178. PMID: 25540325.

Vittori A, Breda C, Repici M, Orth M, Roos RA, Outeiro TF, Giorgini F, Hollox EJ; REGISTRY investigators of the European Huntington's Disease Network. Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease. Hum Mol Genet. 2014 Jun 15;23(12):3129-37. PMID: 24452335; PMCID: PMC4030768.

ALS

King IN, Yartseva V, Salas D, Kumar A, Heidersbach A, Ando DM, Stallings NR, Elliott JL, Srivastava D, Ivey KN. The RNA-binding protein TDP-43 selectively disrupts microRNA-1/206 incorporation into the RNA-induced silencing complex. J Biol Chem. 2014 May 16;289(20):14263-71. PMID: 24719334; PMCID: PMC4022891.

SMA

Rossor AM, Oates EC, Salter HK, Liu Y, Murphy SM, Schule R, Gonzalez MA, Scoto M, Phadke R, Sewry CA, Houlden H, Jordanova A, Tournev I, Chamova T, Litvinenko I, Zuchner S, Herrmann DN, Blake J, Sowden JE, Acsadi G, Rodriguez ML, Menezes MP, Clarke NF, Auer Grumbach M, Bullock SL, Muntoni F, Reilly MM, North KN. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Brain. 2015 Feb;138(Pt 2):293-310. PMID: 25497877; PMCID: PMC4306822.

Additional relevant to neurodegenerative disease

Manayi A, Saeidnia S, Gohari AR, Abdollahi M. Methods for the discovery of new anti-aging products--targeted approaches. Expert Opin Drug Discov. 2014 Apr;9(4):383-405. PMID: 24494592.

Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M, Sanz E, Li Z, Hui J, Graham BH, Quintana A, Bellen HJ. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell. 2015 Jan 15;160(1-2):177-90. PMID: 25594180; PMCID: PMC4377295. From the abstract: "Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here, we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity in neurons leading to LD accumulation in glia ... "

Methylene blue and single oxygen explored in a fly model of tauopathy

Sheik Mohideen S, Yamasaki Y, Omata Y, Tsuda L, Yoshiike Y. Nontoxic singlet oxygen generator as a therapeutic candidate for treating tauopathies. Sci Rep. 2015 Jun 1;5:10821. PMID: 26027742; PMCID: PMC4450544.

From the abstract: "Methylene blue (MB) inhibits the aggregation of tau, a main constituent of neurofibrillary tangles. However, MB's mode of action in vivo is not fully understood. MB treatment reduced the amount of sarkosyl-insoluble tau in Drosophila that express human wild-type tau. MB concurrently ameliorated the climbing deficits of transgenic tau flies to a limited extent and diminished the climbing activity of wild-type flies. MB also decreased the survival rate of wild-type flies. Based on its photosensitive efficacies, we surmised that singlet oxygen generated through MB under light might contribute to both the beneficial and toxic effects of MB in vivo. ... Our findings indicate that singlet oxygen generators with little toxicity may be suitable drug candidates for treating tauopathies."

Flies and neurodegeneration--research report on A beta 43 toxicity in flies and review of findings from fly models of tauopathies

Burnouf S, Gorsky MK, Dols J, Grönke S, Partridge L. Aβ(43) is neurotoxic and primes aggregation of Aβ(40) in vivo. Acta Neuropathol. 2015 Apr 11. PMID: 25862636.

From the abstract: "... Besides the well-studied Aβ40 and Aβ42 species, recent data have raised the possibility that Aβ43 peptides might be instrumental in AD pathogenesis, because they are frequently observed in both dense and diffuse amyloid plaques from human AD brains and are highly amyloidogenic in vitro. However, whether Aβ43 is toxic in vivo is currently unclear. Using Drosophila transgenic models of amyloid pathology, we show that Aβ43 peptides are mainly insoluble and highly toxic in vivo ... Altogether, our study demonstrates high pathogenicity of Aβ43 species in vivo and supports the idea that Aβ43 contributes to the pathological events leading to neurodegeneration in AD."

Sun M, Chen L. Studying Tauopathies in Drosophila: A Fruitful Model. Exp Neurol. 2015 Apr 7. pii: S0014-4886(15)00105-3. PMID: 25862286.

From the abstract: "... summarize key features of transgenic Drosophila models of tauopathies and ... insights into disease mechanisms as well as therapeutic implications gained from the fruit fly models."

Autophagy and neurodenenerative disease

Bakhoum MF, Bakhoum CY, Ding Z, Carlton SM, Campbell GA, Jackson GR. Evidence for autophagic gridlock in aging and neurodegeneration. Transl Res. 2014 Feb 3. pii: S1931-5244(14)00048-6. PMID: 24561013.

Autolysosomes & neurodegeneration. Recent review.

Ambegaokar SS, Jackson GR. The downward spiral of tau and autolysosomes: a new hypothesis in neurodegeneration. Autophagy. 2012 Jul 1;8(7):1144-5. PMID: 22635052; PMCID: PMC3429552.

Fly screening & Alzheimer's disease. Recent report.

Shulman JM, Imboywa S, Giagtzoglou N, Powers MP, Hu Y, Devenport D, Chipendo P, Chibnik LB, Diamond A, Perrimon N, Brown NH, De Jager PL, Feany MB. Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms. Hum Mol Genet. 2013 Oct 9. PMID: 24067533.

Relevant review--fly models & tauopathies

Cowan CM, Mudher A. Are tau aggregates toxic or protective in tauopathies? Front Neurol. 2013;4:114. PMID: 23964266; PMCID: PMC3741634.

Effects of a microtubule-stabilizing drug on fly model of tauopathy. Recent report.

Quraishe S, Cowan CM, Mudher A. NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy. Mol Psychiatry. 2013 Apr 16. PMID: 23587881.

Two reports involving human tau-based fly disease models. Recent report.

Xiong Y, Zhao K, Wu J, Xu Z, Jin S, Zhang YQ. HDAC6 mutations rescue human tau-induced  microtubule defects in Drosophila. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4604-9. doi: 10.1073/pnas.1207586110. PubMed PMID: 23487739; PubMed Central PMCID: PMC3606981.

Wu TH, Lu YN, Chuang CL, Wu CL, Chiang AS, Krantz DE, Chang HY. Loss of vesicular dopamine release precedes tauopathy in degenerative dopaminergic neurons in a Drosophila model expressing human tau. Acta Neuropathol. 2013 Mar 15. PubMed PMID: 23494099.

Tau oligomers and disease. Recent review.

This recent review includes information from fly and mammalian models.
Cowan CM, Quraishe S, Mudher A. What is the pathological significance of tau oligomers? Biochem Soc Trans. 2012 Aug;40(4):693-7. doi: 10.1042/BST20120135. PMID: 22817718.

AD fly model and mitochondria. Recent report.

Open access paper using a fly model of Alzhemer's Disease.

Iijima-Ando K, Sekiya M, Maruko-Otake A, Ohtake Y, Suzuki E, Lu B, Iijima KM. Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease-Related Tau Phosphorylation Via PAR-1. PLoS Genet. 2012 Aug;8(8):e1002918. PubMed PMID: 22952452.

Mitochondria and neurodegeneration. Recent Report.

A breaking report newly implicates mitochondrial dynamics in neurodegenerative disease.

Duboff B, Götz J, Feany MB. Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo. Neuron. 2012 Aug 23;75(4):618-32. PubMed PMID: 22920254

Fly model used (from the Materials and Methods): "Our Drosophila model of tauopathy is based on expression of either wild-type or FTDP-17 linked mutant forms of tau in neurons using the UAS/GAL4 bipartite expression system (Brand and Perrimon, 1993) and a panneuronal driver (elav-GAL4). In these studies, we predominantly express human tau carrying the R406W mutation ... To examine mitochondrial morphology in our model, we coexpressed tau with mitochondrially localized GFP (mitoGFP) in neurons of the adult brain."

Update: this review article looks relevant: Itoh K, Nakamura K, Iijima M, Sesaki H. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol. 2013 Feb;23(2):64-71. PMID: 23159640; PMCID: PMC3558617.