# A decrease in Fkbp52 alters autophagosome maturation and A152T-tau clearance in vivo

Emilie Lesport, Lucie Commeau, Mélanie Genet, Etienne-Emile Baulieu,

Marcel Tawk, Julien Giustiniani

► To cite this version:

Emilie Lesport, Lucie Commeau, Mélanie Genet, Etienne-Emile Baulieu, Marcel Tawk, et al. A decrease in Fkbp52 alters autophagosome maturation and A152T-tau clearance in vivo. Frontiers in Cellular Neuroscience, 2024, 18, pp.1425222. 10.3389/fncel.2024.1425222. inserm-05009941

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OPEN ACCESS

EDITED BY
Laura Segatori,
Rice University, United States

REVIEWED BY
Mireille Rossel,
Institut National de la Santé et de la
Recherche Médicale (INSERM), France
Ping-Chung Chen,
St. Jude Children's Research Hospital,
United States

*CORRESPONDENCE

Emilie Lesport

emilie.lesport@inserm.fr

Marcel Tawk

marcel.tawk@inserm.fr

Julien Giustiniani

julien.giustiniani@inserm.fr

¹These authors share last authorship

RECEIVED 29 April 2024

ACCEPTED 15 July 2024

PUBLISHED 25 July 2024

CITATION

Lesport E, Commeau L, Genet M, Baulieu E-E, Tawk M and Giustiniani J (2024) A decrease in Fkbp52 alters autophagosome maturation and A152T-tau clearance *in vivo*. *Front. Cell. Neurosci.* 18:1425222.
doi: 10.3389/fncel.2024.1425222

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© 2024 Lesport, Commeau, Genet, Baulieu, Tawk and Giustiniani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# A decrease in Fkbp52 alters autophagosome maturation and A152T-tau clearance *in vivo*

Emilie Lesport¹,²*, Lucie Commeau¹, Mélanie Genet¹, Etienne-Emile Baulieu¹,², Marcel Tawk²*† and Julien Giustiniani¹,²*†

¹Institut Professeur Baulieu, INSERM U1195, Kremlin-Bicêtre, France, ²INSERM U1195, Université Paris-Saclay, Kremlin-Bicêtre, France

The failure of the autophagy-lysosomal pathway to clear the pathogenic forms of Tau exacerbates the pathogenesis of tauopathies. We have previously shown that the immunophilin FKBP52 interacts both physically and functionally with Tau, and that a decrease in FKBP52 protein levels is associated with Tau deposition in affected human brains. We have also shown that FKBP52 is physiologically present within the lysosomal system in healthy human neurons and that a decrease in FKBP52 expression alters perinuclear lysosomal positioning and Tau clearance during Tau-induced proteotoxic stress *in vitro*. In this study, we generate a zebrafish *fkbp4* loss of function mutant and show that axonal retrograde trafficking of Lamp1 vesicles is altered in this mutant. Moreover, using our transgenic *HuC::mCherry-EGFP-LC3* line, we demonstrate that the autophagic flux is impaired in *fkbp4* mutant embryos, suggesting a role for Fkbp52 in the maturation of autophagic vesicles. Alterations in both axonal transport and autophagic flux are more evident in heterozygous rather than homozygous *fkbp4* mutants. Finally, taking advantage of the previously described A152T-Tau transgenic fish, we show that the clearance of pathogenic A152T-Tau mutant proteins is slower in *fkbp4+/−* mutants in comparison to *fkbp4+/+* larvae. Altogether, these results indicate that Fkbp52 is required for the normal trafficking and maturation of lysosomes and autophagic vacuoles along axons, and that its decrease is sufficient to hinder the clearance of pathogenic Tau *in vivo*.

KEYWORDS

tau, tauopathies, lysosomes, autophagy, FKBP52, zebrafish

## Introduction

Tauopathies are neurodegenerative diseases characterized by abnormal deposition of Tau proteins within the brain of affected patients. In these diseases, including Alzheimer's disease (AD), Tau becomes hyperphosphorylated and acquires abnormal conformation resulting in the formation of toxic oligomers and intracellular aggregates (Gotz et al., 2019).

The failure of degradative pathways such as the ubiquitin proteasome system or the autophagy-lysosomal pathway (ALP) to clear the pathogenic forms of Tau participates in the pathogenesis of neurodegenerative diseases (Chesser et al., 2013; Fleming et al., 2022). Macro-autophagy (here after named autophagy) is a mechanism by which cytoplasmic compounds become engulfed into double-membraned vesicles called autophagosomes which ultimately
<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>FIGURE 1</figcaption></figure>

Generation of *fkbp4* mutant zebrafish. (A) Position of the CRISPR/Cas9 target site (light green) and PAM sequence (dark green) within exon 2 of the *Danio rerio* *fkbp4* gene. The 1 bp insertion (red) on the mutant allele induces a frameshift and a premature stop codon (orange). (B) Structural domains of the WT Fkbp52 protein and of the "+1" mutant Fkbp52 protein. FK1: peptidyl-prolyl isomerase (PPlase) domain. FK2: PPlase-like domain. TPR: tetratricopeptide repeat domain. CaM: putative calmodulin binding site. (C) Representative immunoblot and resulting quantification showing Fkbp52 levels in WT, *fkbp4*<sup>+/-</sup> and *fkbp4*<sup>-/-</sup> embryos. Actin was used as loading control.

described (Mikdache et al., 2021). Primers are listed in
Supplementary Table S1 (Li et al., 2023).

Statistical analyses

Statistical analyses were performed using GraphPad Prism 7.0.
Unpaired Student's *t*-tests were used when only 2 groups of values
with gaussian distribution were compared. For comparison of more
than two groups, Anova or Kruskal–Wallis test followed by multiple
comparisons test were used. *p*-values lower than 0.05 were considered
significant. *p*<0.05, **p**<0.01, ***p**<0.001, and ****p**<0.001.

Results

Fkbp52 mutant larvae are viable and have
no external phenotype

We have previously shown that FKBP52 is present in the lysosomal
system of neurons from human and murine samples and that the
activity of the ALP was affected by FKBP52 knock-down *in vitro*
(Meduri et al., 2016; Chambraud et al., 2021). To investigate the
function of Fkbp52 in autophagy *in vivo*, we chose to use the
transparent zebrafish larvae that offer a unique opportunity to monitor

the temporal and functional activity of proteins (Boueid et al., 2020).
We generated a loss of function mutant of the *Danio rerio* *fkbp4* gene
encoding Fkbp52, using CRISPR/Cas9 technology. The introduced
mutation created a frameshift leading to a premature stop codon and
the loss of Fkbp52 protein in homozygous embryos as revealed by
Western blot (Figure 1).

Homozygous mutant embryos developed normally and were
undistinguishable from WT fish. However, as they reached adulthood,
*fkbp4*⁻/⁻ males were mostly sterile while homozygous females were all
fertile. As a result, maternal-zygotic *fkbp4*⁻/⁻ embryos could only
be obtained as part of the progeny of homozygous females crossed
with heterozygous males, that we hereafter refer to as ‘mutant’
clutches.

Retrograde transport of Lamp1 vesicles is
accelerated in *fkbp4* mutant zebrafish

It has been shown that FKBP52, in association with the protein
chaperone HSP90 and dynein motor, is implicated in the retrograde
transport and nuclear translocation of different proteins. This includes
the glucocorticoid receptor, the transcription factor p53 and the
human telomerase reverse transcriptase hTERT (Galigniana et al.,
2004; Wochnik et al., 2005; Jeong et al., 2016). Knowing that the
axonal trafficking of autophagic vesicles also relies on dynein motor
<figure><img src="image_6.png" /><figcaption>FIGURE 2</figcaption></figure>

A decrease in Fkbp52 impacts the retrograde velocity of Lamp1-positive vesicles in spinal cord axons. (A) Representative still images of time-lapse imaging at 48 hpf in control, *fkbp4<sup>+/-</sup>* and *fkbp4<sup>-/-</sup>* embryos injected with *pT2-HuC:Lamp1-mEGFP*; white arrows and red arrowheads delineate the anterograde and retrograde transport of Lamp1-positive vesicles, respectively. Scale bar, 20 µm. (B) Quantification of anterograde and retrograde velocity of Lamp1-positive vesicles along axons of spinal cord in WT (*n* = 11), *fkbp4<sup>+/-</sup>* (*n* = 5) and *fkbp4<sup>-/-</sup>* (*n* = 6) embryos from 3 independent experiments. Analysis includes ~12 tracked Lamp1 vesicles per embryo (Kruskal–Wallis, Dunn's multiple comparisons test). Results are shown as mean ± SEM.

complex (Maday et al., 2014), we wondered whether Fkbp52 could
play a role in their transport along microtubules. We chose to monitor
endolysosomal vesicles using Lamp1 as a marker. Zygotes were
injected with the *pT2-HuC:Lamp1-mGFP* construct and isolated
Lamp1-positive vesicles were tracked along individual axons in the
spinal cord at 48 hpf (Figure 2). In WT embryos, as expected, the
anterograde transport was significantly faster than the retrograde
transport (1.27 µm/s ± 0.044 and 1.0865 µm/s ± 0.051 respectively)
(Drerus and Nechiporuk, 2013; Boecker et al., 2020). No significant
difference was observed between WT and *fkbp4* mutant embryos
regarding the anterograde transport of Lamp1-positive vesicles
(1.187 µm/s ± 0.069 and 1.516 µm/s ± 0.101 for *fkbp4*<sup>+/-</sup> and *fkbp4*<sup>-/-</sup>
respectively). By contrast, we observed a significant increase in the
mean velocity of Lamp1-positive vesicles moving retrogradely in
*fkbp4*<sup>-/-</sup> embryos (1.35 µm/s ± 0.066) compared to WT. Unexpectedly,
the same alteration of the retrograde transport of Lamp1-positive

vesicles was also observed in *fkbp4*<sup>+/-</sup> embryos (1.531 µm/s ± 0.105).
Using a second *fkbp4* mutant fish line that we similarly generated
using Cas9-mutagenesis, we also found that the mean retrograde
velocity of Lamp1-positive vesicles was significantly increased in
heterozygous mutants compared to WT (Supplementary Figure S1).

These results indicate that the pool of Lamp1-positive vesicles
moving toward the cell body is affected by a decrease in Fkbp52.

Autolysosomes are less abundant in neurons of *fkbp4* mutant zebrafish

The regulated transport of lysosomes and AVs along axons is
tightly linked to their maturation and any alteration in this process
could hinder autophagic flux (Tamminen and Cai, 2017; Mathew and
Koushika, 2022).
To monitor the autophagic flux within neurons, we generated a new zebrafish transgenic line expressing the mCherry-EGFP fluorescent tandem fused to Lc3, a marker of AVs, under control of the pan-neuronal promoter HuC. The mCherry-EGFP-Lc3 reporter allowed us to discriminate between autophagosomes which appear as yellow vesicles (mCherry-positive and EGFP-positive) and autolysosomes where only the mCherry fluorescence remains after quenching of the EGFP signal due to the acidification of the vesicular lumen (Kimura et al., 2007).

*Tg(HuC::mCherry-EGFP-Lc3)* embryos, hereafter named *HCGL* embryos, showed a mosaic expression of the transgene, but yellow and red AVs were easily visible and distinguishable in labelled neurons at 48 hpf (Supplementary Figure S2). As expected, cell soma contained virtually only red autolysosomes, whereas both red and yellow AVs were observed along axonal projections.

To validate the use of this new transgenic line to study autophagic flux, we treated *HCGL* embryos with Bafilomycin A1, a known lysosomal inhibitor that blocks the fusion of autophagosomes with lysosomes (Fodor et al., 2017). A specific region within the hindbrain showing axonal projections rich in Lc3-positive vesicles was selected to count the number of yellow immature versus red mature AVs (Supplementary Figures S2B–D). As expected, the percentage of mature autolysosomes relative to the total Lc3-positive vesicles was significantly decreased in Bafilomycin-treated *HCGL* embryos compared to control DMSO-treated ones (Figures 3A,B).

Transgenic *HCGL* fish were then crossed with the *fkbp4* mutants to compare the autophagic flux between *fkbp4* mutant and WT embryos. For the studied region, we found an average of 42% ± 12% of autolysosomes relative to total AVs in *fkbp4*<sup>+/+</sup> embryos. This figure was significantly decreased to 32% ± 9% in *fkbp4*<sup>+/-</sup> and 35% ± 10% in *fkbp4*<sup>-/-</sup> mutant embryos (Figures 3C,D). Thus, mature acidic autolysosomes appeared to be less abundant in *fkbp4* mutant embryos, with a slightly sharper decrease in heterozygous rather than homozygous *fkbp4* mutants in comparison to WT.

## The kinetic of pathogenic A152T-tau clearance is reduced in *fkbp4*<sup>+/-</sup> mutants

It has been shown that the clearance of A152T-Tau relies solely on the ALP since the proteasome activity was suppressed in A152T-Tau larvae. Moreover, the clearance of A152T-Tau was slowed following inhibition of lysosomes with ammonium chloride and conversely accelerated by pharmacological induction of autophagy using clonidine or rilmenidine (Lopez et al., 2017).

We reasoned that a reduced proportion of mature autolysosomes in *fkbp4* mutant larvae could hinder the clearance of A152T-Tau. To test this hypothesis, we took advantage of the photoconvertible protein Dendra fused to A152T-Tau in the *Tg(UAS::Dendra-Tau A152T)* line to monitor the kinetics of Tau clearance *in vivo*. A specific region of the spinal cord in *fkbp4* mutant and WT embryos with matched expression of A152T-Tau was photoconverted at 48 hpf and the decrease in the red fluorescence was assessed 24h and 48h later. *fkbp4*<sup>+/+</sup> larvae showed a mean of 19.4% ± 2.9% of the initial Red-Dendra intensity remaining 24h after photoconversion. This kinetic was not significantly different in *fkbp4*<sup>-/-</sup> larvae, with a mean of 23.4% ± 3.4 and 17.0% ± 2.2% of the initial Red-Dendra intensity,

respectively, remaining 24h and 48h after photoconversion. However, these values were significantly increased in *fkbp4*<sup>+/-</sup> larvae compared to *fkbp4*<sup>+/+</sup> controls at both time points (27.1% ± 5.2% at 24h and 17.4 ± 3.0% at 48h), indicating that the clearance of A152T-Tau was significantly slower in heterozygous fish (Figure 4).

## Discussion

The proper regulation of autophagy is essential for maintaining cellular homeostasis and many studies have implicated autophagy dysregulation in the development of neurodegenerative diseases (Fujikake et al., 2018). By understanding the distinct functions of autophagy in the nervous system and its main regulators, we could better understand how to manipulate autophagy for therapeutic benefit (Djajadikerta et al., 2020). We have previously shown that FKBP52 co-localizes with autophagy-lysosomal markers and an early pathological Tau isoform in AD neurons (Meduri et al., 2016), and that FKBP52 knock down impaired the lysosomal clustering induced by Tau proteotoxicity *in vitro* (Chambraud et al., 2021). Based on these results, we hypothesized that Fkbp52 could impact on physiological lysosomal activity and the autophagy dependent, pathological A152T-Tau clearance.

To test our hypothesis, we took advantage of the translucent zebrafish larvae to follow the dynamic of ALP vesicles in a live organism. It is known that FKBP52, through its interaction with the dynein complex, is required for the nuclear translocation of glucocorticoid receptor (GR) (Wochnik et al., 2005), and can drive the retrograde transport of different cargos along microtubules (Silverstein et al., 1999; Galigniana et al., 2004; Jeong et al., 2016). Consequently, FKBP52 could contribute to the retrograde transport of lysosomes also known to be orchestrated by dynein. To test this, we monitored the movement of Lamp1 vesicles along axons of zebrafish spinal cord, expecting a less processive retrograde transport in the absence of Fkbp52. Surprisingly, we found that the retrograde velocity of Lamp1 vesicles was significantly increased in *fkbp4* mutant zebrafish. Lamp1-positive vesicles in retrograde movement are in fact a heterogenous pool of organelles with different velocities, namely lysosomes, late endosomes, and autolysosomes, that could be differently affected by Fkbp52 deficiency. Indeed, maturing autolysosomes could be part of the subpopulation of Lamp1 vesicles moving retrogradely with a relatively low velocity, as suggested by Lie et al. (2021). Accordingly, the reduced proportion of autolysosomes along axons of *fkbp4* mutants could lead to an overrepresentation of faster moving organelles in comparison to controls, resulting in a biased increase of the mean velocity.

Our work also provides insights into the role of Fkbp52 in autophagic flux *in vivo*. We here generated the *Tg(HuC::mCherry-EGFP-map1lc3B)* line to monitor the autophagic flux within neurons. By analyzing the autophagosomes/autolysosomes ratios along axons of *HCGL* fish, we observed a defective maturation of AVs in *fkbp4* mutants, consistent with our previous results in cultured neuronal cells (Chambraud et al., 2021). Although the underlying mechanism remains to be understood, we hypothesize that Fkbp52 may play a role in controlling the fusions of AVs with lysosomes, which are necessary for their maturation, possibly through fine tuning lysosomal trafficking. Alternatively, Fkbp52 could play a more direct role in the maturation process, by facilitating the acidification of AVs. For
<figure><img src="image_7.png" /><figcaption>FIGURE 3</figcaption></figure>

The maturation of autophagosomes is impaired in *fkbp4* mutants. (A,C) Representative z-projections of the hindbrain region were Lc3-positive vesicles were counted in *HGCL* transgenic fish, either treated with DMSO or Bafilomycin A1 (A) or crossed with *fkbp4* mutants (C). Top panels: mCherry; middle panels: EGFP; bottom panels: merged of top and middle panels. Autophagosomes have both red and green signal (yellow arrowheads) whereas autolysosomes show red only signal (white arrows). Scale bar, 5 µm (B) Quantification of the percentage of autolysosomes and autophagosomes relative to the total number of autophagic vacuoles in DMSO treated (n = 5 embryos) and Bafilomycin A1 treated *HGCL* embryos (n = 8 embryos) *HGCL* embryos from one experiment representative of 3 (t-test with Welch's correction, *p* = 0.0332). (D) Quantification of the percentage of autolysosomes relative to the total number of autophagic vacuoles in control *fkbp4*4⁺/+/*HGCL⁺ (n = 27), *fkbp4*4⁺/-/*HGCL⁺ (n = 22, **p* = 0.0021 compared to control) and *fkbp4*4⁻/-/*HGCL⁺ (n = 23 embryos, \*p* = 0.0373 compared to control) embryos from 3 independent experiments (One-way ANOVA with Tukey's multiple comparison). Results are shown as mean ± SD.
A

<figure><img src="image_8.png" /></figure>

B

<figure><img src="image_9.png" /><figcaption>FIGURE 4</figcaption></figure>

The clearance of A152T-Tau is significantly slower in *fkbp4<sup>+/-</sup>* mutants. (A) Representative images showing z-stack projections of the photoconverted neurons with Green-Dendra signal just before photoconversion (left panels) and Red-Dendra signal just after photoconversion, 24 h and 48 h later (right panels) in *fkbp4<sup>+/-</sup>, *fkbp4<sup>+/-</sup>*, and *fkbp4<sup>-/-</sup>* embryos expressing Dendra-Tau A152T. Scale bar, 10 µm. (B) The remaining intensity of the initial Red-Dendra signal was calculated as percentage of the initial intensity 24 h and 48 h post photoconversion in *fkbp4<sup>+/-</sup>*, *fkbp4<sup>+/-</sup>*, and *fkbp4<sup>-/-</sup>* larvae with similar A152T-Tau expression (*fkbp4<sup>+/-</sup>*; *n* = 16, average expression 143 ± 31; *fkbp4<sup>+/-</sup>*; *n* = 11, average expression 141 ± 26; *fkbp4<sup>-/-</sup>*; *n* = 5, average expression 141 ± 47) from 4 independent experiments (*fkbp4<sup>+/-</sup>* vs. *fkbp4<sup>+/-</sup>* at 24 h: *****p < 0.0001; *fkbp4<sup>+/-</sup>* vs. *fkbp4<sup>+/-</sup>* at 48 h: **p = 0.0012; two-way ANOVA with Tukey's multiple comparison). Results are shown as mean ± SD.

instance, it has been described that FKBP52 is able to interact with different transient receptor potential (TRP) channels and modulate their activities in cultured cells (Gkika et al., 2006; Shim et al., 2009). Along the same vein, FKBP52 might modulate the activity of the mucolipin TRP channel which plays a critical role in lysosome acidification and membrane fusion events with late endosomes and AVs (Soyombo et al., 2006; Dong et al., 2008; Li et al., 2013).

Together, our results indicate that Fkbp52 deficiency results in a significant decrease in the percentage of mature autolysosomes being transported to the neuronal cell body. This likely impairs the autophagic degradation of toxic proteins, since we observe a reduced clearance of A152T-Tau, known to be degraded by autophagy (Lopez et al., 2017; Caballero et al., 2018), in *fkbp4* heterozygous mutant. This result is consistent with our previous finding whereby a decrease in FKBP52 induces an accumulation of P301S-Tau in dorsal root ganglia neurons from mice under long-term proteotoxic stress (Chambraud et al., 2021).

It is important to note that the defects observed in heterozygous *fkbp4* mutants are globally enhanced in comparison to homozygous ones. This raises the possibility of a genetic compensation in embryos lacking Fkbp52. The non-sense mediated decay of mutant *fkbp4* mRNA could activate a compensatory network, possibly members of the Fkbp family and/or other proteins, leading to a milder phenotype, similar to other knockout zebrafish mutants (Rossi et al., 2015; Zhu et al., 2017; El-Brolosy et al., 2019; Diofano et al., 2020). Indeed, the mRNA levels of *fkbp5* (coding for Fkbp51), known to be functionally antagonistic to Fkbp52 in some instances (Wochnik et al., 2005), are significantly reduced in *fkbp4<sup>-/-</sup>* mutants in comparison to heterozygous mutants (Supplementary Figure S3). Whether these two proteins act as antagonists in this particular context is still to be determined.

Interestingly, we observed no obvious defects in *fkbp4<sup>+/-</sup>* adult fish whereas *fkbp4<sup>-/-</sup>* adult males were mostly sterile. This phenotype is unlikely to be linked to the function of Fkbp52 in the ALP, but rather to its role as a cochaperone of steroid hormone receptors. Indeed, male FKBP52 knock out mice show several defects in their reproductive tissues that are linked to androgen receptor insensitivity (Cheung-Flynn et al., 2005; Chen et al., 2010). We repeatedly observed that most of the *fkbp4<sup>-/-</sup>* males do not display the expected courtship behavior during mating, consistent with the phenotype described upon genetic disruption of androgen signaling in zebrafish (Yong et al., 2017; Shu et al., 2020).

Altogether, our findings reveal an important role for Fkbp52 in the transport of lysosomes, the maturation of autophagic vacuoles and the clearance of pathogenic Tau proteins *in vivo*. Therefore, the reduced levels of FKBP52 in the brains of AD or FTLD-Tau patients might contribute to the accumulation of toxic proteins by impairing autophagy, further worsening the pathogenesis of the disease. Preventing FKBP52 decrease or restoring its lost function in affected neurons might represent a new potential therapeutic approach to slow down progression of Tau pathology.

## Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

## Ethics statement

The animal studies were approved by DDPP Val de Marne, France, under license number F 94-043-013. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the owners for the participation of their animals in this study.

## Author contributions

EL: Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing, Visualization. LC: Investigation, Methodology, Writing – review & editing. MG: Investigation, Methodology, Writing – review & editing. E-EB: Funding acquisition, Project administration, Writing – review & editing. MT: Conceptualization, Funding acquisition,
Investigation, Supervision, Writing - review & editing. JG: Conceptualization, Formal analysis, Funding acquisition, Investigation, Supervision, Writing - review & editing.

## Funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by Institut Baulieu, the Fondation Vaincre Alzheimer (FR-18055p), INSERM and Paris-Saclay University.

## Acknowledgments

We thank Herwig Baier (Max Planck Institute for biological intelligence, Germany) for the Tg(HuC::Gal4) zebrafish and David C. Rubinzstein (University of Cambridge, United Kingdom) for the Tg(UAS::Dendra-Tau A152T) zebrafish. We thank Beatrice Chambraud, Geri Meduri, Corentin Daguinot and Cindy Degerny for useful discussions and technical help. We acknowledge Institut Professeur Baulieu for financial support to EL, LC, MG, and JG.

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## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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## Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fncel.2024.1425222/full#supplementary-material

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