Reference Report

Reference
Citation	Iijima-Ando, K., Hearn, S.A., Shenton, C., Gatt, A., Zhao, L., Iijima, K. (2009). Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease. PLoS ONE 4(12): e8310. (Export to RIS)
FlyBase ID	FBrf0209556
Publication Type	Research paper
PubMed ID	20016833
PubMed Abstract	The amyloid-beta 42 (Abeta42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which Abeta42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Abeta42 induces mitochondrial mislocalization, which contributes to Abeta42-induced neuronal dysfunction in a transgenic Drosophila model. In the Abeta42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial damage or neurodegeneration. In contrast, organization of microtubule or global axonal transport was not significantly altered at this stage. Abeta42-induced behavioral defects were exacerbated by genetic reductions in mitochondrial transport, and were modulated by cAMP levels and PKA activity. Levels of putative PKA substrate phosphoproteins were reduced in the Abeta42 fly brains. Importantly, perturbations in mitochondrial transport in neurons were sufficient to disrupt PKA signaling and induce late-onset behavioral deficits, suggesting a mechanism whereby mitochondrial mislocalization contributes to Abeta42-induced neuronal dysfunction. These results demonstrate that mislocalization of mitochondria underlies the pathogenic effects of Abeta42 in vivo.
DOI	10.1371/journal.pone.0008310
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Language of Publication	English
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Publication Type	Journal
Abbreviation	PLoS ONE
Title	PLoS ONE
Publication Year	2006-
ISBN/ISSN	1932-6203
Data from Reference
Alleles (19)
	Avic\GFP^{S65T.Scer\UAS.T:Ivir\HA1,T:Hsap\mito} CrebB^d.hs CrebB^S162 dnc¹ Hsap\APP^{Aβ1-42.Scer\UAS.cIa} Hsap\SNCA^Scer\UAS.cFa milt^GD8116 Miro^Sd32 Mmus\Cd8a^{Scer\UAS.T:Avic\GFP} Pka-C1^KK108966 Pka-R2^EP2162 Pka-R2^EY11550 Pka-R2^GD15709 rut¹ Scer\GAL4^Cha.7.4 Scer\GAL4^elav-C155 Scer\GAL4^ey-OK107 Syt1^{Scer\UAS.T:Avic\GFP-EGFP} αTub84B^{Scer\UAS.P\T.T:Avic\GFP-S65C}
Constructs (11)
	P{Cha-GAL4.7.4} P{GD8116} P{GD15709} P{hs-CrebB-17A.d} P{KK108966} P{UAS-Aβ42.I} P{UAS-Hsap\SNCA.F} P{UAS-mCD8::GFP.L} P{UAS-mito-HA-GFP.AP} P{UASp-GFPS65C-αTub84B} P{UAS-syt.eGFP}
Genes (17)
	Avic\GFP CrebB dnc Hsap\APP Hsap\SNCA milt Miro Mmus\Cd8a mt:CoI mt:CoIII mt:Cyt-b Pka-C1 Pka-R2 rut Scer\GAL4 Syt1 αTub84B
Insertions (3)
	P{EP}Pka-R2^EP2162 P{GawB}elav^C155 P{GawB}ey^OK107