New lessons on TDP‐43 from old <i>N. furzeri</i> killifish

Louka, Alexandra; Bagnoli, Sara; Rupert, Jakob; Esapa, Benjamin; Tartaglia, Gian Gaetano; Cellerino, Alessandro; Pastore, Annalisa; Tozzini, Eva Terzibasi

doi:10.1111/acel.13517

Cited by 10 publications

(7 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, we did not observe differential expression of genes related to other neurodegenerative diseases, such as Alzheimer-related genes mapta (encoding tau protein) or appa (encoding amyloid beta precursor protein) and the frontotemporal dementia/amyotrophic lateral sclerosis gene tardbp (encodes Tdp-43 protein). This could indicate that features reported in the aged killifish brain, such as amyloid beta-plaques and Tdp-43 stress granules (Bagnoli et al, 2022; Bergmans et al, 2023a; de Bakker and Valenzano, 2023; Louka et al, 2022; Matsui et al, 2019), are not manifesting in the ageing killifish retina, although investigation at the protein level would be required to determine this.…”

Section: Resultsmentioning

confidence: 99%

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Bergmans,

Noel,

Masin

et al. 2024

Preprint

View full text Add to dashboard Cite

Age-related vision loss caused by neurodegenerative pathologies in the retina is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.HighlightsThe aged killifish retina displays several ageing hallmarks, such as oxidative stress, gliosis, and inflammageing, at the transcriptome level.Risk genes for neurodegenerative disorders show dysregulation in the old killifish retina.All vertebrate retinal cell types are present in the killifish retina.Transcriptional dysregulation in the aged killifish retina is observed across cell types.Cell type-specific transcriptomic changes across age highlight increased stress response.

show abstract

Section: Resultsmentioning

confidence: 99%

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Bergmans,

Noel,

Masin

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Therefore, we conducted a comprehensive analysis of proteostasis in the aging brain of the short-lived killifish Nothobranchius furzeri . We chose killifish because of its accelerated aging and spontaneous emergence of neurodegenerative phenotypes ( 3 – 8 )…”

Section: Main Textmentioning

confidence: 99%

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Di Fraia,

Marino,

Lee

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Protein homeostasis declines both in aging and neurodegenerative diseases, yet our understanding of how aging affects brain proteostasis is still limited. Here, we measured and integrated the effects of aging on the transcriptome, translatome, and multiple layers of the proteome in the brain of a short-lived killifish. We found that aging causes a decoupling between transcript and protein levels leading to, e.g., decreased abundance of proteins enriched in basic amino acids independent of mRNA changes. Chronic proteasome impairment in vivo induces aging signatures in lysosomes and mitochondria. However, it does not recapitulate the age-related decoupling between transcripts and proteins. Instead, increased translation pausing and reduced ribosome levels reprogram protein synthesis independently of transcription. These changes in protein biogenesis likely reduce the availability of key protein complexes and contribute to the remodeling of organelles in older brains.

show abstract

“…Tools to advance genetic interrogation of the killifish have been developed, including a sequenced genome (Reichwald et al, 2015; Valenzano et al, 2015) and Tol2 transgenesis (Allard et al, 2013; Hartmann and Englert, 2012; Valenzano et al, 2011), as well as CRISPR/Cas9-mediated knock-out (Harel et al, 2015) and CRISPR/Cas13-mediated knock-down (Kushawah et al, 2020). This genetic toolkit has enabled discoveries about the mechanisms of aging (Astre et al, 2022a; Bradshaw et al, 2022; Chen et al, 2022; Harel et al, 2022; Louka et al, 2022; Matsui et al, 2019; Smith et al, 2017; Van Houcke et al, 2021b), regeneration (Vanhunsel et al, 2022a; Vanhunsel et al, 2021; Vanhunsel et al, 2022b; Wang et al, 2020), evolution (Cui et al, 2019; Sahm et al, 2017; Singh et al, 2021; Willemsen et al, 2020), development (Abitua et al, 2021; Dolfi et al, 2019), and ‘suspended animation’ (Hu et al, 2020; Singh et al, 2021).…”

Section: Main Textmentioning

confidence: 99%

Rapid and precise genome engineering in a naturally short-lived vertebrate

Nath

Bedbrook

Nagvekar

et al. 2022

Preprint

View full text Add to dashboard Cite

The African turquoise killifish is a powerful vertebrate system to study complex phenotypes at scale, including aging and age-related disease. Here we develop a rapid and precise CRISPR/Cas9-mediated knock-in approach in the killifish. We show its efficient application to precisely insert fluorescent reporters of different sizes at various genomic loci, to drive cell-type- and tissue-specific expression. This knock-in method should allow the establishment of humanized disease models and the development of cell-type-specific molecular probes for studying complex vertebrate biology.

show abstract

New lessons on TDP‐43 from old N. furzeri killifish

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 71 publications

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Rapid and precise genome engineering in a naturally short-lived vertebrate

Contact Info

Product

Resources

About