Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology

Tsujikawa, Koyo; Hamanaka, Kohei; Riku, Yuichi; Hattori, Yukio; Hara, Norikazu; Iguchi, Yohei; Ishigaki, Shinsuke; Hashizume, Akira; Miyatake, Satoko; Sobue, Gen; Miyazaki, Yu; Kataoka, Mayumi; Li, Jiayi; Yasui, Keizo; Kuru, Satoshi; Koike, Haruki; Kobayashi, Kenta; Sahara, Naruhiko; Ozaki, Norio; Yoshida, Mari; Kakita, Akiyoshi; Saito, Yuko; Iwasaki, Yasushi; Miyashita, Akinori; Iwatsubo, Takeshi; Ikeuchi, Takeshi; Miyata, Takaki; Matsumoto, Naomichi; Sahashi, Kentaro; Katsuno, Masahisa

doi:10.1126/sciadv.abm5029

Cited by 16 publications

(28 citation statements)

References 66 publications

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“…A previous study by Tsujikawa et al (2022) did not find any AD-associated changes of FLNA levels. However, the sample size of the current study is three and a half times the size of the one that was used in this study (N = 57 vs. N = 16).…”

Section: Discussionmentioning

confidence: 51%

“…Previous studies in cellular and animal models including ours ( Levert et al, 2022 , in press; Tsujikawa et al, 2022 ) revealed that upon FLNA overexpression, an increase of tau protein levels and phosphorylation, two events reported in early stages of AD, were observed ( Braak et al, 2011 ). Based on this, we anticipated that FLNA alterations might be associated with tau accumulation and hyperphosphorylation prior to the formation of NFTs.…”

Section: Resultsmentioning

confidence: 61%

“…FLNA may also contribute to tau pathology in the absence of Aβ. From cell culture experiments, Tsujikawa et al (2022) reported that higher FLNA levels increased tau protein levels, phosphorylation and insolubility, while its reduction was shown to decrease these effects on tau. Collectively the above observations indicate that the abnormal function of FLNA could be crucial for inducing the neuropathological processes of AD.…”

Section: Introductionmentioning

confidence: 99%

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Evidence of Filamin A loss of solubility at the prodromal stage of neuropathologically-defined Alzheimer’s disease

Aumont

Tremblay

Levert

et al. 2022

Front. Aging Neurosci.

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IntroductionAlzheimer’s disease (AD) is a multifactorial disorder diagnosed through the assessment of amyloid-beta (Aβ) and tau protein depositions. Filamin A (FLNA) could be a key partner of both Aβ and tau pathological processes and may be an important contributor to AD progression. The main aim of this study was to describe the differences in FLNA levels across clinicopathologic groups.MethodsFrom parietal cortex samples of 57 individuals (19 with no cognitive impairment (NCI), 19 mild cognitively impaired (MCI) and 19 with dementia) from the Religious Orders Study (ROS), we quantified total tau, phosphorylated tau (pTau), FLNA, synaptophysin, vesicular acetylcholine transporters (VAChT) and choline acetyltransferase (ChAT) by Western blot. Aβ42 and neuritic plaques (NP) were quantified by ELISA and Bielschowsky silver impregnation, respectively. AD staging was determined using ABC method combining Thal, Braak and the CERAD staging. From this, clinicopathologic stages of AD were established by subdividing subjects with neuropathological AD between preclinical AD, prodromal AD and AD dementia (ADD). Receiver operating characteristics analyses were performed to predict AD neuropathology from FLNA quantifications.ResultsInsoluble FLNA was significantly and positively correlated with Aβ42, NP, Thal stages, ABC scores and AD clinicopathologic stages (p < 0.05 False discovery rate-corrected). No correlation of FLNA with tau measures was found. Insoluble FLNA levels were significantly higher in the prodromal AD, ADD and intermediate ABC groups. This was consistent with significantly lower levels of soluble FLNA specifically in prodromal AD. Insoluble (AUC: 0.830) and soluble FLNA levels (AUC: 0.830) as well as the ratio of soluble over insoluble FLNA (AUC: 0.852), were excellent predictors of prodromal AD among subjects with MCI from the ROS cohort.DiscussionWe observed opposite level changes between insoluble and soluble FLNA in prodromal AD. As this stage coincides with the appearance of cognitive symptoms, this may be a key event in the transition from preclinical to prodromal AD. Insoluble FLNA could be useful to identify prodromal AD among subjects with an MCI, indicating that it might be a hallmark of prodromal AD.

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Section: Discussionmentioning

confidence: 51%

Section: Resultsmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

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Evidence of Filamin A loss of solubility at the prodromal stage of neuropathologically-defined Alzheimer’s disease

Aumont

Tremblay

Levert

et al. 2022

Front. Aging Neurosci.

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“…RACK1 is actually suggested modulating VIME by controlling STAT1, STAT3, AP-1, HIF1A, and SMAD3 transcription factors, PKC and AKT kinases as well as the protein phosphatase 2A (PP2A catalytic), and the actin-network component filamin-A. Notably, all these interactors are known to play key roles in NS physiology and their dysfunctions have been associated with several neuropathies, including tauopathies [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

Section: Resultsmentioning

confidence: 99%

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

Vantaggiato

Shaba

Carleo

et al. 2022

IJMS

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Krabbe disease (KD) is a rare autosomal recessive disorder caused by mutations in the galactocerebrosidase gene (GALC). Defective GALC causes aberrant metabolism of galactolipids present almost exclusively in myelin, with consequent demyelinization and neurodegeneration of the central and peripheral nervous system (NS). KD shares some similar features with other neuropathies and heterozygous carriers of GALC mutations are emerging with an increased risk in developing NS disorders. In this work, we set out to identify possible variations in the proteomic profile of KD-carrier brain to identify altered pathways that may imbalance its homeostasis and that may be associated with neurological disorders. The differential analysis performed on whole brains from 33-day-old twitcher (galc −/−), heterozygous (galc +/−), and wild-type mice highlighted the dysregulation of several multifunctional factors in both heterozygous and twitcher mice. Notably, the KD-carrier mouse, despite its normal phenotype, presents the deregulation of vimentin, receptor of activated protein C kinase 1 (RACK1), myelin basic protein (MBP), 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP), transitional endoplasmic reticulum ATPase (VCP), and N-myc downstream regulated gene 1 protein (NDRG1) as well as changes in the ubiquitinated-protein pattern. Our findings suggest the carrier may be affected by dysfunctions classically associated with neurodegeneration: (i) alteration of (mechano) signaling and intracellular trafficking, (ii) a generalized affection of proteostasis and lipid metabolism, with possible defects in myelin composition and turnover, and (iii) mitochondrion and energy supply dysfunctions.

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“…Filamin proteins, the first family of nonmuscle actin-binding proteins, are cytoplasmic proteins that cross-link cortical actin to form dynamic 3D structures. Each Filamin gene family member contains one or two filamin-type immunoglobulin (Ig) domains in animals [ 11 , 12 , 13 ]. The domain is constructed from a tandem repeat of 100 residue motifs rich in glycine and proline, followed by two β-sheets arranged into an Ig-like fold [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Relationships and Divergence of Filamin Gene Family Involved in Development and Stress in Cotton (Gossypium hirsutum L.)

Wang

Zhu

et al. 2022

Genes

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Filamin protein is characterized by an N-terminal actin-binding domain that is followed by 24 Ig (immunoglobulin)-like repeats, which act as hubs for interactions with a variety of proteins. In humans, this family has been found to be involved in cancer cell invasion and metastasis and can be involved in a variety of growth signal transduction processes, but it is less studied in plants. Therefore, in this study, 54 Filamin gene family members from 23 plant species were investigated and divided into two subfamilies: FLMN and GEX2. Subcellular localization showed that most of the Filamin gene family members were located in the cell membrane. A total of 47 Filamin gene pairs were identified, most of which were whole-genome copies. Through the analyses of cis-acting elements, expression patterns and quantitative fluorescence, it was found that GH_ A02G0519 and GH_ D02G0539 are mainly expressed in the reproductive organs of upland cotton, and their interacting proteins are also related to the fertilization process, whereas GH_A02G0216 and GH_D02G0235 were related to stress. Thus, it is speculated that two genes of the GEX2 subfamily (GH_A02G0519 and GH_D02G0539) may be involved in the reproductive development of cotton and may affect the fertilization process of cotton. This study provides a theoretical basis for the further study of the cotton Filamin gene family.

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Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology

Cited by 16 publications

References 66 publications

Evidence of Filamin A loss of solubility at the prodromal stage of neuropathologically-defined Alzheimer’s disease

Evidence of Filamin A loss of solubility at the prodromal stage of neuropathologically-defined Alzheimer’s disease

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

Evolutionary Relationships and Divergence of Filamin Gene Family Involved in Development and Stress in Cotton (Gossypium hirsutum L.)

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