While a number of genome-wide association studies have identified microtubule-associated protein tau as a strong risk factor for Parkinson’s disease (PD), little is known about the mechanism through which human tau can predispose an individual to this disease. Here, we demonstrate that expression of human wild-type tau is sufficient to disrupt the survival of dopaminergic neurons in a Drosophila model. Tau triggers a synaptic pathology visualized by vesicular monoamine transporter-pHGFP that precedes both the age-dependent formation of tau-containing neurofibrillary tangle-like pathology and the progressive loss of DA neurons, thereby recapitulating the pathological hallmarks of PD. Flies overexpressing tau also exhibit progressive impairments of both motor and learning behaviors. Surprisingly, contrary to common belief that hyperphosphorylated tau could aggravate toxicity, DA neuron degeneration is alleviated by expressing the modified, hyperphosphorylated tauE14. Together, these results show that impairment of VMAT-containing synaptic vesicle, released to synapses before overt tauopathy may be the underlying mechanism of tau-associated PD and suggest that correction or prevention of this deficit may be appropriate targets for early therapeutic intervention.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1105-x) contains supplementary material, which is available to authorized users.

Leucine-rich repeat kinase 2 (LRRK2) is a complex kinase and mutations in LRRK2 are perhaps the most common genetic cause of Parkinson's disease (PD). However, the identification of the normal physiological function of LRRK2 remains elusive. Here, we show that LRRK2 protects neurons against apoptosis induced by the Drosophila genes grim, hid and reaper. Genetic dissection reveals that Akt is the critical downstream kinase of LRRK2 that phosphorylates and inhibits FOXO1, and thereby promotes survival. Like human LRRK2, Drosophila lrrk also promotes neuron survival; lrrk loss-of-function mutant displays reduced cell numbers, which can be rescued by LRRK2 expression. Importantly, LRRK2 G2019S and LRRK2 R1441C mutants impair the ability of LRRK2 to activate Akt, and fail to prevent apoptotic death. Ectopic expression of a constitutive active form of Akt hence is sufficient to rescue this functional deficit. These data establish that LRRK2 can protect neurons from apoptotic insult through a survival pathway in which LRRK2 signals to activate Akt, and then inhibits FOXO1. These results might indicate that a LRRK-Akt therapeutic pathway to promote neuron survival and to prevent neurodegeneration in Parkinson's disease.

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15Spatial orientation plays a crucial role in animal navigation. Recent studies of tethered 16Drosophila melanogaster (fruit fly) in a virtual reality setting showed that the 17 orientation is encoded in the form of an activity bump, i.e. localized neural activity, in 18 the torus-shaped ellipsoid body (EB). Moreover, a fly can maintain working memory of 19 its orientation with a stable and persistent activity bump in the absence of any visual 20 cue, and update the memory in accordance with changes of the body orientation by 21shifting the location of the bump. Although the neural circuit that is responsible for 22shifting the bump has been extensively studied lately, how the nervous system shifts 23 the bump while maintains its stability and persistence is poorly understood. We 24 investigated this question using free moving fruit flies in a spatial orientation memory 25 task, and manipulated two EB subsystems, the P circuit, which has been suggested 26 for the stabilization function, and the C circuit, which has been suggested for the 27 updating function but was largely overlooked. We discovered that overactivating either 28 circuit produced distinct behavioral deficits, confirming that the two circuits play 29 important but different roles in the orientation working memory. Furthermore, 30 suppressing either circuit disrupted the memory, suggesting that the C or P circuit 31 alone is not sufficient to maintain the orientation working memory. We reproduced the 32 observations with a spiking neural network model of EB and demonstrated that spatial 33 orientation working memory requires coordinated activation of the stabilizing and 34 updating neural processes in different movement modes. 35 36 Keywords 37 Central complex, ellipsoid body, spatial orientation memory, working memory, Buridan's 38 paradigm, Drosophila melanogaster 39 40 Introduction 41Maintaining spatial orientation is a crucial cognitive capability required for animal 42 navigation [1,2], and understanding the detailed neural mechanisms of spatial orientation 43 is of great interest to researchers in the fields of neurobiology [3][4][5] or neuromorphic 44 engineering [6][7][8]. In recent years, significant progress has been made in identifying the 45 neural circuits that support spatial orientation [9] in the central complex of Drosophila 46 melanogaster [10,11]. The central complex has long been associated with short-term 47Recently, a model of the EB-PB circuits proposed in Su et al., (2017) was built strictly 64 based on connectomic data and provided a detailed picture of the neural circuit 65 interactions underlying spatial orientation and its working memory [15]. The model 66suggests the involvement of two sets of coupled circuits that connect the EB and PB. One 67 set that consists of EIP (or E-PG) and PEI neurons forms symmetric recurrent connections, 68 and the other set that consists of EIP and PEN (or P-EN) forms asymmetric recurrent 69 4 connections [20,21]. The symmetric circuit, named the C circuit in this paper, forms an 70 attract...