A Drosophila model of GSS syndrome suggests defects in active zones are responsible for pathogenesis of GSS syndrome

Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyangdong Dongangu, Anyang, Gyeonggi-Do, Republic of Korea.
Human Molecular Genetics (Impact Factor: 6.39). 11/2010; 19(22):4474-89. DOI: 10.1093/hmg/ddq379
Source: PubMed


We have established a Drosophila model of Gerstmann–Sträussler–Scheinker (GSS) syndrome by expressing mouse prion protein (PrP) having leucine substitution
at residue 101 (MoPrPP101L). Flies expressing MoPrPP101L, but not wild-type MoPrP (MoPrP3F4), showed severe defects in climbing ability and early death. Expressed MoPrPP101L in Drosophila was differentially glycosylated, localized at the synaptic terminals and mainly present as deposits in adult brains. We found
that behavioral defects and early death of MoPrPP101L flies were not due to Caspase 3-dependent programmed cell death signaling. In addition, we found that Type 1 glutamatergic
synaptic boutons in larval neuromuscular junctions of MoPrPP101L flies showed significantly increased numbers of satellite synaptic boutons. Furthermore, the amount of Bruchpilot and Discs
large in MoPrPP101L flies was significantly reduced. Brains from scrapie-infected mice showed significantly decreased ELKS, an active zone matrix
marker compared with those of age-matched control mice. Thus, altered active zone structures at the molecular level may be
involved in the pathogenesis of GSS syndrome in Drosophila and scrapie-infected mice.

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Available from: Jin-Kyu Choi
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    • "Recently, several non-mammalian neurodegeneration models have been employed (21–23) and in particular, expression of PrPC and PrPSC in Drosophila or Caenorhabditis elegans allows investigations of prion function in host organisms that do not have a direct prion ortholog (24–29). PrPC can convert into PrPSC in adult Drosophila causing neurodegeneration and expression of a mutated PrPC (PrPP101L) is sufficient to mimic neurodegenerative phenotypes in adult Drosophila (25,30). PrPC can modulate synaptic transmission (31) including potentiation of acetylcholine release at the mouse NMJ (32), whereas PrPC-KO mice exhibit reduced inhibitory release (14). "
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    ABSTRACT: The cellular prion protein (PrPC) has been implicated in several neurodegenerative diseases as a result of protein misfolding. In humans, prion disease occurs typically with a sporadic origin where uncharacterized mechanisms induce spontaneous PrPC misfolding leading to neurotoxic PrP-scrapie formation (PrPSC). The consequences of misfolded PrPC signalling are well characterized but little is known about the physiological roles of PrPC and its involvement in disease. Here we investigated wild-type PrPC signalling in synaptic function as well as the effects of a disease-relevant mutation within PrPC (proline-to-leucine mutation at codon 101). Expression of wild-type PrPC at the Drosophila neuromuscular junction leads to enhanced synaptic responses as detected in larger miniature synaptic currents which are caused by enlarged presynaptic vesicles. The expression of the mutated PrPC leads to reduction of both parameters compared with wild-type PrPC. Wild-type PrPC enhances synaptic release probability and quantal content but reduces the size of the ready-releasable vesicle pool. Partially, these changes are not detectable following expression of the mutant PrPC. A behavioural test revealed that expression of either protein caused an increase in locomotor activities consistent with enhanced synaptic release and stronger muscle contractions. Both proteins were sensitive to proteinase digestion. These data uncover new functions of wild-type PrPC at the synapse with a disease-relevant mutation in PrPC leading to diminished functional phenotypes. Thus, our data present essential new information possibly related to prion pathogenesis in which a functional synaptic role of PrPC is compromised due to its advanced conversion into PrPSC thereby creating a lack-of-function scenario.
    Full-text · Article · Apr 2014 · Human Molecular Genetics
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    • "In a previous study, we generated several independent TG lines that express wild-type mouse-PrP tagged with the human/hamster 3F4 epitope at residues 109M-112M (Mo-PrP 3F4 ) using a Gal4/UAS expression system. The Mo-PrP 3F4 TG Drosophila lines did not show any obvious neuropathological abnormalities, even though other TG lines expressing similar amounts of a GSS mutant form of Mo-PrP 3F4 that contains an additional proline to lysine substitution at residue 101 (Mo-PrP P101L ) manifested progressive neuropathological symptoms [12]. To investigate the in vivo function of wild-type PrP, UAS-Mo-PrP 3F4 TG lines were crossed with Tubulin (Tub)-Gal4 driver flies to induce ubiquitous expression of Mo-PrP 3F4 . "
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    ABSTRACT: To investigate the in vivo functions of normal prion protein (PrP) in Drosophila, we utilized characterized transgenic flies expressing 3F4-tagged mouse PrP (Mo-PrP3F4). The neurotoxicity of pathogenic Machado-Joseph Disease (MJD) glutamine (Q) 78 and 127Q proteins were enhanced by the co-expression of Mo-PrP3F4 in the fly eyes, while the eyes of controls flies and flies expressing Mo-PrP3F4 alone or together with MJD-Q27 or 20Q proteins did not show any defect. Susceptibilities to H2O2, paraquat, and Dithiothreitol (DTT) were altered in Mo-PrP3F4 flies. In addition, Mo-PrP3F4 flies were significantly more susceptible to the perturbation of autophagy signaling by an autophagy inhibitor, 3-methyladenine (3-MA), and inducer, LiCl. Taken together, our data suggest that Mo-PrP3F4 may enhance the neurotoxicity of pathogenic Poly-Q proteins by perturbing oxidative and autophagy signaling.
    Full-text · Dataset · Apr 2013
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    • "Gerstmann–Sträussler–Scheinker (GSS) syndrome is one type of fetal prion disease that causes prominent neurodegeneration in the cerebellum and cerebral cortex (Ghetti et al., 1995; Mead, 2006). In a Drosophila model of GSS syndrome, the amount of the active zone protein Bruchpilot was significantly reduced, indicating that an active zone deficiency may be involved in the progress of this disease (Choi et al., 2010). However , it is currently unclear whether patients with GSS syndrome show this active zone deficiency or not. "
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    ABSTRACT: Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density) during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs), the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS), active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and β-adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated.
    Full-text · Article · Feb 2012 · Frontiers in Molecular Neuroscience
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