Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation

Kim, Jae Hong; Rahman, Habibur; Park, Donghwi; Jo, Myungjin; Kim, Hyung Jun; Suk, Kyoungho

doi:10.3390/cells10030676

Cited by 12 publications

(7 citation statements)

References 94 publications

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“…Primary astrocytes with TDP-43 inclusions accumulated more lipid droplets, activated aerobic glycolysis, and downregulated lactate transporters, resulting in decreased metabolic support for MNs and neurotoxicity (Velebit et al, 2020). TDP-43 inclusion in the cytoplasm also induced astrocyte inflammation and activation, secreting pro-inflammatory factors (IL-1β, IL-6, and TNFα) and causing neurodegeneration and neuroinflammation (Lee et al, 2020;Kim et al, 2021).…”

Section: Tar Dna-binding Protein 43 and Astrocytesmentioning

confidence: 99%

Astrocytes in Neurodegeneration: Inspiration From Genetics

Huang

Shang

2022

Front. Neurosci.

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Despite the discovery of numerous molecules and pathologies, the pathophysiology of various neurodegenerative diseases remains unknown. Genetics participates in the pathogenesis of neurodegeneration. Neural dysfunction, which is thought to be a cell-autonomous mechanism, is insufficient to explain the development of neurodegenerative disease, implying that other cells surrounding or related to neurons, such as glial cells, are involved in the pathogenesis. As the primary component of glial cells, astrocytes play a variety of roles in the maintenance of physiological functions in neurons and other glial cells. The pathophysiology of neurodegeneration is also influenced by reactive astrogliosis in response to central nervous system (CNS) injuries. Furthermore, those risk-gene variants identified in neurodegenerations are involved in astrocyte activation and senescence. In this review, we summarized the relationships between gene variants and astrocytes in four neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), and provided insights into the implications of astrocytes in the neurodegenerations.

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Section: Tar Dna-binding Protein 43 and Astrocytesmentioning

confidence: 99%

Astrocytes in Neurodegeneration: Inspiration From Genetics

Huang

Shang

2022

Front. Neurosci.

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“…Recent studies have found that TDP-43 is regulated by nuclear localisation signal (NLS) and nuclear export signal (NES) motifs; apart from its neuronal regulation activity, it also constantly shuttles between the cytoplasm and the nucleus [14,15]. Transcription and splicing are also involved in the courses of neurons' differentiation and apoptosis to maintain the stability of mRNA, which are the neuronal activity response to modulate neuronal plasticity [16][17][18].…”

Section: The Research Development Of Ftd Neuropathological Featurementioning

confidence: 99%

The Advance on Frontotemporal Dementia (FTD)’s Neuropathology and Molecular Genetics

Wang

Zhou

2022

Mediators of Inflammation

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The morbidity of frontotemporal dementia (FTD), one of the most prevalent dementias praccox, is second to Alzheimer disease (AD). It is different with AD that FTD has a rapider course and a higher mortality. FTD has not yet been fully understood in terms of etiology or pathogenesis, but genetic factors are believed to be involved. In this paper, we were committed to providing a comprehensive overview to FTD in aspects of the neuropathology features and the relevant molecular genetics advances, so that there would be insights to those researchers in search of novel approaches in FTD diagnosis and treatment.

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“…Genetic screens for modifiers of TDP-43 toxicity in the yeast system identified proteins involved in TDP-43 on toxicity [ 3 , 11 , 12 , 13 , 14 , 15 ]. Indeed, the finding that deletion or overexpression of PBP1, respectively reduces or enhances TDP-43 toxicity led to the discovery that PBP1′s human homolog, ATXN2 , is associated with ALS risk.…”

Section: Introductionmentioning

confidence: 99%

TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects

Park

Liebman

2022

Viruses

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When human TDP-43 is overexpressed in yeast it is toxic and forms cytoplasmic aggregates. The mechanism of this toxicity is unknown. Genetic screens for TDP-43 toxicity modifiers in the yeast system previously identified proteins, including PBP1, that enhance TDP-43 toxicity. The determination in yeast that deletion of PBP1 reduces TDP-43 toxicity while overexpression enhances toxicity, led to the discovery that its human homolog, ATXN2, is associated with ALS risk. Thus, the yeast system has relevance to human disease. We now show that deletion of a new yeast gene, tip41Δ, likewise suppresses TDP-43 toxicity. We also found that TDP-43 overexpression and toxicity is associated with reduced autophagy. This is consistent with findings in other systems that increasing autophagy reduces TDP-43 toxicity and is in contrast to a report of enhanced autophagy when TDP-43 was overexpressed in yeast. Interestingly, we found that deletions of PBP1 and TIP41, which reduced TDP-43 toxicity, eliminated TDP-43′s inhibition of autophagy. This suggests that toxicity of TDP-43 expressed in yeast is in part due to its inhibition of autophagy and that deletions of PBP1 and TIP41 may reduce TDP-43 toxicity by preventing TDP-43 from inhibiting autophagy.

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Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation

Cited by 12 publications

References 94 publications

Astrocytes in Neurodegeneration: Inspiration From Genetics

Astrocytes in Neurodegeneration: Inspiration From Genetics

The Advance on Frontotemporal Dementia (FTD)’s Neuropathology and Molecular Genetics

TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects

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