Publications by authors named "Shabab B Hannan"

6 Publications

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Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone in .

Autophagy 2021 Jan 25:1-15. Epub 2021 Jan 25.

Research Group Synaptic Plasticity, Hertie Institute for Clinical Brain Research, University of Tübingen , Tübingen, Germany.

We investigated in larval and adult models whether loss of the mitochondrial chaperone is sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we studied an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displayed ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of , and . The knockdown of components of the macroautophagy/autophagy machinery or overexpression of human broadly rescued larval and adult phenotypes, while disease-associated variants did not. Overexpression of or promotion of autophagy exacerbated defects. AEL: after egg laying; AZ: active zone; brp: bruchpilot; Csp: cysteine string protein; dlg: discs large; eEJPs: evoked excitatory junctional potentials; GluR: glutamate receptor; HO: hydrogen peroxide; mEJP: miniature excitatory junctional potentials; MT: microtubule; NMJ: neuromuscular junction; PD: Parkinson disease; : PTEN-induced putative kinase 1; PSD: postsynaptic density; SSR: subsynaptic reticulum; SV: synaptic vesicle; VGlut: vesicular glutamate transporter.
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http://dx.doi.org/10.1080/15548627.2020.1871211DOI Listing
January 2021

The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization.

Sci Rep 2017 03 27;7:38172. Epub 2017 Mar 27.

Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076 Tübingen 72076, Germany.

The kinesin-3 family member KIF1A has been shown to be important for experience dependent neuroplasticity. In Drosophila, amorphic mutations in the KIF1A homolog unc-104 disrupt the formation of mature boutons. Disease associated KIF1A mutations have been associated with motor and sensory dysfunctions as well as non-syndromic intellectual disability in humans. A hypomorphic mutation in the forkhead-associated domain of Unc-104, unc-104, impairs active zone maturation resulting in an increased fraction of post-synaptic glutamate receptor fields that lack the active zone scaffolding protein Bruchpilot. Here, we show that the unc-104mutation causes defects in synaptic transmission as manifested by reduced amplitude of both evoked and miniature excitatory junctional potentials. Structural defects observed in the postsynaptic compartment of mutant NMJs include reduced glutamate receptor field size, and altered glutamate receptor composition. In addition, we observed marked loss of postsynaptic scaffolding proteins and reduced complexity of the sub-synaptic reticulum, which could be rescued by pre- but not postsynaptic expression of unc-104. Our results highlight the importance of kinesin-3 based axonal transport in synaptic transmission and provide novel insights into the role of Unc-104 in synapse maturation.
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http://dx.doi.org/10.1038/srep38172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366810PMC
March 2017

The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation.

Front Cell Neurosci 2016 5;10:207. Epub 2016 Sep 5.

Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of TübingenTübingen, Germany; Schaller Research Group at the University of Heidelberg and DKFZ, Proteostasis in Neurodegenerative Disease (B180), German Cancer Research CenterHeidelberg, Germany.

Mutations in the kinesin-3 family member KIF1A have been associated with hereditary spastic paraplegia (HSP), hereditary and sensory autonomic neuropathy type 2 (HSAN2) and non-syndromic intellectual disability (ID). Both autosomal recessive and autosomal dominant forms of inheritance have been reported. Loss of KIF1A or its homolog unc-104 causes early postnatal or embryonic lethality in mice and Drosophila, respectively. In this study, we use a previously described hypomorphic allele of unc-104, unc-104(bris) , to investigate the impact of partial loss-of-function of kinesin-3 on synapse maturation at the Drosophila neuromuscular junction (NMJ). Unc-104(bris) mutants exhibit structural defects where a subset of synapses at the NMJ lack all investigated active zone (AZ) proteins, suggesting a complete failure in the formation of the cytomatrix at the active zone (CAZ) at these sites. Modulating synaptic Bruchpilot (Brp) levels by ectopic overexpression or RNAi-mediated knockdown suggests that the loss of AZ components such as Ca(2+) channels and Liprin-α is caused by impaired kinesin-3 based transport rather than due to the absence of the key AZ organizer protein, Brp. In addition to defects in CAZ assembly, unc-104(bris) mutants display further defects such as depletion of dense core and synaptic vesicle (SV) markers from the NMJ. Notably, the level of Rab3, which is important for the allocation of AZ proteins to individual release sites, was severely reduced at unc-104(bris) mutant NMJs. Overexpression of Rab3 partially ameliorates synaptic phenotypes of unc-104(bris) larvae, suggesting that lack of presynaptic Rab3 contributes to defects in synapse maturation.
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http://dx.doi.org/10.3389/fncel.2016.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011141PMC
September 2016

Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models.

J Neurochem 2016 Apr 11;137(1):12-25. Epub 2016 Feb 11.

Schaller Research Group at the University of Heidelberg and DKFZ, Proteostasis in Neurodegenerative Disease (B180), German Cancer Research Center, Heidelberg, Germany.

Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) long before the identification of mutations in the Microtubule-associated protein tau (MAPT) gene, encoding the tau protein, in a different neurodegenerative disease called Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the MAPT gene associated with FTDP-17 highlighted that dysfunctions in tau alone are sufficient to cause neurodegeneration. Invertebrate models have been diligently utilized in investigating tauopathies, contributing to the understanding of cellular and molecular pathways involved in disease etiology. 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. The simplicity of handling invertebrate models combined with the availability of a diverse range of experimental resources make these models, in particular Drosophila a powerful invertebrate screening tool. Consequently, several large-scale screens have been performed using Drosophila, to identify modifiers of tau toxicity. The screens have revealed not only common cellular and molecular pathways, but in some instances the same modifier has been independently identified in two or more screens suggesting a possible role for these modifiers in regulating tau toxicity. The purpose of this review is to discuss the genetic modifier screens on tauopathies performed in Drosophila and C. elegans models, and to highlight the common cellular and molecular pathways that have emerged from these studies. Here, we summarize results of tau toxicity screens providing mechanistic insights into pathological alterations in tauopathies. Key pathways or modifiers that have been identified are associated with a broad range of processes including, but not limited to, phosphorylation, cytoskeleton organization, axonal transport, regulation of cellular proteostasis, transcription, RNA metabolism, cell cycle regulation, and apoptosis. 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. In this review, we combined and summarized several large-scale modifier screens performed in invertebrate models to identify modifiers of tau toxicity. A summary of the screens show that diverse cellular processes are implicated in the modification of tau toxicity. Kinases and phosphatases are the most predominant class of modifiers followed by components required for cellular proteostasis and axonal transport and cytoskeleton elements.
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http://dx.doi.org/10.1111/jnc.13532DOI Listing
April 2016

Impaired retrograde transport by the Dynein/Dynactin complex contributes to Tau-induced toxicity.

Hum Mol Genet 2015 Jul 20;24(13):3623-37. Epub 2015 Mar 20.

Department of Neurology, University Hospital, RWTH Aachen, Germany,

The gene mapt codes for the microtubule-associated protein Tau. The R406W amino acid substitution in Tau is associated with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) characterized by Tau-positive filamentous inclusions. These filamentous Tau inclusions are present in a group of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD). To gain more insights into the pathomechanism of tauopathies, we performed an RNAi-based large-scale screen in Drosophila melanogaster to identify genetic modifiers of Tau[R406W]-induced toxicity. A collection of RNAi lines, putatively silencing more than 7000 genes, was screened for the ability to modify Tau[R406W]-induced toxicity in vivo. This collection covered more than 50% of all protein coding fly genes and more than 90% of all fly genes known to have a human ortholog. Hereby, we identified 62 genes that, when silenced by RNAi, modified Tau-induced toxicity specifically. Among these 62 modifiers were three subunits of the Dynein/Dynactin complex. Analysis on segmental nerves of fly larvae showed that pan neural Tau[R406W] expression and concomitant silencing of Dynein/Dynactin complex members synergistically caused strong pathological changes within the axonal compartment, but only minor changes at synapses. At the larval stage, these alterations did not cause locomotion deficits, but became evident in adult flies. Our data suggest that Tau-induced detrimental effects most likely originate from axonal rather than synaptic dysfunction and that impaired retrograde transport intensifies detrimental effects of Tau in axons. In conclusion, our findings contribute to the elucidation of disease mechanisms in tauopathies like FTDP-17 or AD.
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http://dx.doi.org/10.1093/hmg/ddv107DOI Listing
July 2015

In vivo imaging of intact Drosophila larvae at sub-cellular resolution.

J Vis Exp 2010 Sep 10(43). Epub 2010 Sep 10.

Junior Research Group Synaptic Plasticity, Hertie Institute for Clinical Brain Research, University of Tübingen.

Recent improvements in optical imaging, genetically encoded fluorophores and genetic tools allowing efficient establishment of desired transgenic animal lines have enabled biological processes to be studied in the context of a living, and in some instances even behaving, organism. In this protocol we will describe how to anesthetize intact Drosophila larvae, using the volatile anesthetic desflurane, to follow the development and plasticity of synaptic populations at sub-cellular resolution. While other useful methods to anesthetize Drosophila melanogaster larvae have been previously described, the protocol presented herein demonstrates significant improvements due to the following combined key features: (1) A very high degree of anesthetization; even the heart beat is arrested allowing for lateral resolution of up to 150 nm, (2) a high survival rate of >90% per anesthetization cycle, permitting the recording of more than five time-points over a period of hours to days and (3) a high sensitivity enabling us in 2 instances to study the dynamics of proteins expressed at physiological levels. In detail, we were able to visualize the postsynaptic glutamate receptor subunit GluR-IIA expressed via the endogenous promoter in stable transgenic lines and the exon trap line FasII-GFP. (4) In contrast to other methods the larvae can be imaged not only alive, but also intact (i.e. non-dissected) allowing observation to occur over a number of days. The accompanying video details the function of individual parts of the in vivo imaging chamber, the correct mounting of the larvae, the anesthetization procedure, how to re-identify specific positions within a larva and the safe removal of the larvae from the imaging chamber.
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http://dx.doi.org/10.3791/2249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157860PMC
September 2010