Exploring common genetic contributors to neuroprotection from amyloid pathology

Mahoney, Emily R.; Dumitrescu, Logan; Ramanan, Vijay K.; Engelman, Corinne D.; Deming, Yuetiva; Albert, Marilyn; Johnson, Sterling C.; Zetterberg, Henrik; Blennow, Kaj; Vemuri, Prashanthi; Jefferson, Angela L.; Hohman, Timothy J.

doi:10.1093/braincomms/fcac066

Cited by 13 publications

(7 citation statements)

References 78 publications

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“…have been linked to AD and other neurodegenerative diseases. 99,138,[140][141][142][143][144][145][146][147][148] Our transcriptome data strongly suggests that splicing and transcriptional abnormalities due to TDP-43 acetylation impacts synaptic plasticity, neurotransmission, and neuronal survival pathways in the TDP-43 KQ/KQ model, which overlaps with abnormalities found in human FTLD-TDP patients. We suspect that this prominent RNA signature may underlie the cognitive decline in TDP-43 KQ/KQ neocortex and hippocampus.…”

Section: Discussionsupporting

confidence: 53%

RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy

Necarsulmer,

Simon,

Evangelista

et al. 2023

Preprint

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TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.

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Section: Discussionsupporting

confidence: 53%

RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy

Necarsulmer,

Simon,

Evangelista

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Similarly, Nos1, encoding the neuronal nitric oxide synthase (nNOS) protein that regulates LTP and synaptic plasticity via the production of nitric oxide 142,143 , showed aberrant splicing patterns in TDP-43 KQ/KQ mice. Importantly, all of these synaptic regulators (Nos1, Lrp8, Argef2, Sema5b) and other signi cantly altered splice variants (e.g., Adipor2, Mapk14, Smarca4, Sort1, Mapt) have all been linked to AD and other neurodegenerative diseases 101,141,[143][144][145][146][147][148][149][150][151] . Altogether, our transcriptome data strongly suggests that splicing and transcriptional abnormalities due to TDP-43 acetylation impacts synaptic plasticity, neurotransmission, and neuronal survival pathways in the TDP-43 KQ/KQ model, which overlaps with abnormalities found in human FTLD-TDP patients.…”

Section: Discussionmentioning

confidence: 99%

RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy

Necarsulmer

Simon

Evangelista

et al. 2023

Preprint

View full text Add to dashboard Cite

TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced nuclear TDP-43 foci and loss-of-TDP-43-function in primary mouse and human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.

show abstract

“…Similarly, Nos1, encoding the neuronal nitric oxide synthase (nNOS) protein that regulates LTP and synaptic plasticity via the production of nitric oxide 135,136 , showed aberrant splicing patterns in TDP-43 KQ/KQ mice. Importantly, all of these synaptic regulators (Nos1, Lrp8, Argef2, Sema5b) and other signi cantly altered splice variants (e.g., Adipor2, Mapk14, Smarca4, Sort1, Mapt) have all been linked to AD and other neurodegenerative diseases 98,134,[136][137][138][139][140][141][142][143][144] . Altogether, our transcriptome data strongly suggests that splicing and transcriptional abnormalities due to TDP-43 acetylation impacts synaptic plasticity, neurotransmission, and neuronal survival pathways in the TDP-43 KQ/KQ model, which overlaps with abnormalities found in human FTLD-TDP patients.…”

Section: Discussionmentioning

confidence: 99%

A TDP-43 acetylation-mimic mutation that disrupts RNA-binding drives FTLD-like neurodegeneration in a mouse model of sporadic TDP-43 proteinopathy

Necarsulmer

Simon

Evangelista

et al. 2022

Preprint

View full text Add to dashboard Cite

TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis are neurodegenerative disorders characterized by aggregation and mislocalization of TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced phase-separated TDP-43 foci and loss-of-TDP-43-function in mouse primary neurons and human induced pluripotent stem cell-derived neurons. Mice harboring the TDP-43K145Q mutation recapitulate key hallmarks of FTLD-TDP, including progressive TDP-43 phosphorylation and insolubility, mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study suggests that TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes, many of which modulate synaptic plasticity and stress response signaling. Unraveling this neurodegenerative cascade provides a new paradigm to interrogate FTLD pathogenesis.

show abstract

Exploring common genetic contributors to neuroprotection from amyloid pathology

Cited by 13 publications

References 78 publications

RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy

RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy

RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy

A TDP-43 acetylation-mimic mutation that disrupts RNA-binding drives FTLD-like neurodegeneration in a mouse model of sporadic TDP-43 proteinopathy

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