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

Butzlaff, Malte; Hannan, Shabab B.; Karsten, Peter; Lenz, Sarah; Ng, Josephine; Voßfeldt, Hannes; Prüßing, Katja; Pflanz, Ralf; Schulz, Jörg B.; Rasse, Tobias M.; Voigt, Aaron

doi:10.1093/hmg/ddv107

Cited by 60 publications

(52 citation statements)

References 79 publications

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“…Other putative target proteins identified by our database search for hsa-miR-502-3p are dynactin (dynein activator complex) and superoxide dismutase 2 (SOD2). Both proteins were implicated in AD pathogenesis by multiple studies: SOD2 as one of the key mitochondrial anti-oxidative stress proteins clearing reactive oxygen species (reviewed in [82]), and dynactin as a known complex regulator of dynein binding to cell vesicles to be transported along microtubules, which contributes to tau-induced toxicity [83]. …”

Section: Discussionmentioning

confidence: 99%

Profile of 6 microRNA in blood plasma distinguish early stage Alzheimer’s disease patients from non-demented subjects

et al. 2017

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Alzheimers disease (AD) is the most common age-related dementia. Among its major challenges is identifying molecular signatures characteristic for the early AD stage in patients with Mild Cognitive Impairment (MCI-AD), which could serve for deciphering the AD pathomechanism and also as non-invasive, easy-to-access biomarkers. Using qRT-PCR we compared the microRNA (miRNA) profiles in blood plasma of 15 MCI-AD patients, whose diagnoses were confirmed by cerebrospinal fluid (CSF) biomarkers, with 20 AD patients and 15 non-demented, age-matched individuals (CTR).To minimize methodological variability, we adhered to standardization of blood and CSF assays recommended by the international Joint Programming for Neurodegenerative Diseases (JPND) BIOMARKAPD consortium, and we employed commercially available Exiqon qRT-PCR-assays. In the first screening, we assessed 179 miRNAs of plasma. We confirmed 23 miRNAs reported earlier as AD biomarker candidates in blood and found 26 novel differential miRNAs between AD and control subjects. For representative 15 differential miRNAs, the TargetScan, MirTarBase and KEGG database analysis indicated putative protein targets among such AD hallmarks as MAPT (Tau), proteins involved in amyloidogenic proteolysis, and in apoptosis. These 15 miRNAs were verified in separate, subsequent subject groups. Finally, 6 miRNAs (3 not yet reported in AD context and 3 reported in AD blood) were selected as the most promising biomarker candidates differentiating early AD from controls with the highest fold changes (from 1.32 to 14.72), consistent significance, specificities from 0.78 to 1 and sensitivities from 0.75 to 1. (patent pending, PCT/IB2016/052440).

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Section: Discussionmentioning

confidence: 99%

Profile of 6 microRNA in blood plasma distinguish early stage Alzheimer’s disease patients from non-demented subjects

et al. 2017

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“…We also showed that LC domains in U1-70K were important for aggregation [14] suggesting that the aggregation properties of U1 snRNPs in AD are similar to the aforementioned RNA binding proteins in other neurodegenerative diseases. Furthermore, in two independent screens performed in Drosophila models, genetic manipulation of selected spliceosome components (including the homolog of SNRPB) modulated Tau-induced neurotoxicity in vivo [51,52]. Separately, in a RNA-interference screen conducted in Drosophila cell culture, manipulation of multiple orthologs of U1 snRNP components (i.e., SNRPD2, SNRPD3, SNRNP70 and SNRPB2) influenced A␤ production [53], suggesting the possibility of reciprocal interactions.…”

Section: Discussionmentioning

confidence: 99%

Changes in the detergent-insoluble brain proteome linked to amyloid and tau in Alzheimer's Disease progression

et al. 2016

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Despite a key role of amyloid-beta (Aβ) in Alzheimer’s disease (AD), mechanisms that link Aβ plaques to tau neurofibrillary tangles and cognitive decline still remain poorly understood. The purpose of this study was to quantify proteins in the sarkosyl-insoluble brain proteome correlated with Aβ and tau insolubility in the asymptomatic phase of AD (AsymAD) and through mild cognitive impairment (MCI) and symptomatic AD. Employing label-free mass spectrometry based proteomics, we quantified 2,711 sarkosyl-insoluble proteins across the prefrontal cortex from 35 individual cases representing control, AsymAD, MCI and AD. Significant enrichment of Aβ and tau in AD was observed, which correlated with neuropathological measurements of plaque and tau tangle density, respectively. Pairwise correlation coefficients were also determined for all quantified proteins to Aβ and tau, across the 35 cases. Notably, 6 of the 10 most correlated proteins to Aβ were U1 small nuclear ribonucleoproteins (U1 snRNPs). Three of these U1 snRNPs (U1A, SmD and U1-70K) also correlated with tau consistent with their association with tangle pathology in AD. Thus, proteins that cross-correlate with both Aβ and tau, including specific U1 snRNPs, may have potential mechanistic roles in linking Aβ plaques to tau tangle pathology during AD progression.

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“…Flies were cultured as previously described (Butzlaff et al, 2015). w1118, elav(X)-Gal4, unc-104 d11024 and UAS-Cac-GFP flies were obtained from Bloomington Stock Center.…”

Section: Methodsmentioning

confidence: 99%

“…Larval dissections (mid-3rd instar stage) were performed essentially as previously described (Fuger et al, 2012; Butzlaff et al, 2015). In brief, larvae were dissected using fine dissection scissors in Ca 2+ -free HL3 solution and fixed in 4% paraformaldehyde in PBS either for 3 min (staining with native fluorescent proteins) or for 10 min (for staining with only immunofluorescent labeling).…”

Section: Methodsmentioning

confidence: 99%

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

Zhang

Hannan

Stapper

et al. 2016

Front. Cell. Neurosci.

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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-104bris, to investigate the impact of partial loss-of-function of kinesin-3 on synapse maturation at the Drosophila neuromuscular junction (NMJ). Unc-104bris 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 Ca2+ 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-104bris 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-104bris mutant NMJs. Overexpression of Rab3 partially ameliorates synaptic phenotypes of unc-104bris larvae, suggesting that lack of presynaptic Rab3 contributes to defects in synapse maturation.

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

Cited by 60 publications

References 79 publications

Profile of 6 microRNA in blood plasma distinguish early stage Alzheimer’s disease patients from non-demented subjects

Profile of 6 microRNA in blood plasma distinguish early stage Alzheimer’s disease patients from non-demented subjects

Changes in the detergent-insoluble brain proteome linked to amyloid and tau in Alzheimer's Disease progression

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

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