Optineurin Deficiency and Insufficiency Lead to Higher Microglial TDP-43 Protein Levels

Prtenjača, Nikolina; Rob, Matea; Alam, Mohammed Shafiul; Markovinović, Andrea; Stuani, Cristiana; Buratti, Emanuele; Munitić, Ivana

doi:10.3390/ijms23126829

Cited by 8 publications

(6 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lastly, we checked for the presence of TDP-43 protein aggregation. Because of the reportedly different preferential staining of cytoplasmic aggregates and nuclear TDP-43 by antibodies targeting the C- and N-terminus of TDP-43 26 , we used both antibodies. None of the anti-TDP-43 antibodies detected cytoplasmic aggregates (Supplementary Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, models carrying optineurin C-terminal truncation (Optn 470T ) or point mutation (Optn D477N ), mimicking some ALS patient mutations that disrupt ubiquitin binding, showed no overt neuroinflammation or ALS pathology (at two months, and one year, respectively) 18 , 24 . Isolated primary microglia from the Optn 470T mouse model showed decreased activation of TBK1 and subsequent interferon (IFN)-β production 24 , but no defect in microglial phagocytosis 25 or TDP-43 aggregation 26 . However, detailed characterisation and/or long-term repercussions of the ubiquitin-binding optineurin mutations in the in vivo models are lacking so it is unknown if these models are similar or distinct to Optn −/− mice.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

Prtenjača¹,

Peradinović²,

Markovinović³

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

Optineurin is a multifunctional polyubiquitin-binding protein implicated in inflammatory signalling. Optineurin mutations are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), neurodegenerative diseases characterised by neuronal loss, neuroinflammation, and peripheral immune disbalance. However, the pathogenic role of optineurin mutations is unclear. We previously observed no phenotype in the unmanipulated young optineurin insufficiency mice (Optn470T), designed to mimic ALS/FTD-linked truncations deficient in polyubiquitin binding. The purpose of this study was to investigate whether ageing would trigger neurodegeneration. We performed a neurological, neuropathological, and immunological characterization of ageing wild-type (WT) and Optn470T mice. No motor or cognitive differences were detected between the genotypes. Neuropathological analyses demonstrated signs of ageing including lipofuscin accumulation and microglial activation in WT mice. However, this was not worsened in Optn470T mice, and they did not exhibit TAR DNA-binding protein 43 (TDP-43) aggregation or neuronal loss. Spleen immunophenotyping uncovered T cell immunosenescence at two years but without notable differences between the WT and Optn470T mice. Conventional dendritic cells (cDC) and macrophages exhibited increased expression of activation markers in two-year-old Optn470T males but not females, although the numbers of innate immune cells were similar between genotypes. Altogether, a combination of optineurin insufficiency and ageing did not induce ALS/FTD-like immune imbalance and neuropathology in mice.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

Prtenjača¹,

Peradinović²,

Markovinović³

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Lastly, we checked for the presence of TDP-43 protein aggregation. Because of the reportedly different preferential staining of cytoplasmic and nuclear TDP-43 by antibodies targeting the C- and N-terminus of TDP-43, respectively (26), we used both antibodies. None of the anti-TDP-43 antibodies detected cytoplasmic aggregates (Suppl.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, models carrying optineurin C-terminal truncation (Optn 470T ) or point mutation (Optn D477N ), mimicking some ALS patient mutations that disrupt ubiquitin-binding, showed no overt neuroinflammation or ALS pathology (at two months, and one year, respectively) (17,24). Isolated primary microglia from the Optn 470T mouse model showed decreased activation of TBK1 and subsequent interferon (IFN)-β production (24), but no defect in phagocytosis (25) or TDP-43 aggregation (26). However, detailed characterisation and/or long-term repercussions of the ubiquitin-binding optineurin mutations in the in vivo models are lacking so it is unknown if these models are similar or distinct to Optn -/- mice.…”

Section: Introductionmentioning

confidence: 99%

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

Prtenjača

Peradinović

Markovinović

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Optineurin is a multifunctional polyubiquitin-binding protein implicated in inflammatory signalling. Optineurin mutations are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), neurodegenerative diseases characterised by neuronal loss, neuroinflammation, and peripheral immune disbalance. However, the pathogenic role of optineurin mutations is unclear. We previously observed no phenotype in the unmanipulated young optineurin insufficiency mice (Optn470T), designed to mimic ALS/FTD-linked truncations deficient in polyubiquitin binding. The purpose of this study was to investigate whether ageing would trigger neurodegeneration. We performed a neuroimmune characterization of ageing wild-type (WT) and Optn470T mice. No motor or cognitive differences were detected between the genotypes. Neuropathological analyses demonstrated signs of ageing including lipofuscin accumulation and microglial activation. However, this was not worsened in Optn470T mice, and they did not exhibit TAR DNA-binding protein 43 (TDP-43) aggregation or neuronal loss. Spleen immunophenotyping uncovered T cell immunosenescence at two years but without notable differences between the WT and Optn470T mice. Conventional dendritic cells (cDC) and macrophages exhibited increased expression of activation markers in two-year-old Optn470T males but not females, although the numbers of innate immune cells were similar between genotypes. Altogether, a combination of optineurin insufficiency and ageing did not induce ALS/FTD-like neuropathology in mice.

show abstract

“…ALS can be caused by OPTN gene mutations, which result in cytoplasmic mislocalization, ubiquitination, and accumulation of nuclear TDP-43. Prtenjaca et al (2022) used CRISPR/Cas9 methodology to create OPTN knockout (KO) cell lines for Neuro 2a and NSC-34 neurons and BV2 microglia to investigate the relationship between optineurin and TDP-43. Their research showed that OPTN mutations might lead to elevated levels of TDP-43 protein in microglia when optineurin is absent (Prtenjaca et al, 2022).…”

Section: Amyotrophic Lateral Sclerosis Model Constructionmentioning

confidence: 99%

CRISPR/Cas9: implication for modeling and therapy of amyotrophic lateral sclerosis

Shi

Zhao

et al. 2023

Front. Neurosci.

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a deadly neurological disease with a complicated and variable pathophysiology yet to be fully understood. There is currently no effective treatment available to either slow or terminate it. However, recent advances in ALS genomics have linked genes to phenotypes, encouraging the creation of novel therapeutic approaches and giving researchers more tools to create efficient animal models. Genetically engineered rodent models replicating ALS disease pathology have a high predictive value for translational research. This review addresses the history of the evolution of gene editing tools, the most recent ALS disease models, and the application of CRISPR/Cas9 against ALS disease.

show abstract

Optineurin Deficiency and Insufficiency Lead to Higher Microglial TDP-43 Protein Levels

Abstract: Mutations in optineurin, a ubiquitin-binding adaptor protein, cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease of motor neurons linked to chronic inflammation and protein aggregation [...]

Cited by 8 publications

References 53 publications

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

CRISPR/Cas9: implication for modeling and therapy of amyotrophic lateral sclerosis

Contact Info

Product

Resources

About