Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43

Topic: Brain proteins, microglia and lab models

TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate approximately 35 and approximately 25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.

@article{zhang2007-17898224,
  author  = {Zhang, Y. J. and Xu, Y. F. and Dickey, C. A. and Buratti, E. and Baralle, F. and Bailey, R. and Pickering-Brown, S. and Dickson, D. and others},
  title   = {{Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43}},
  journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
  year    = {2007},
  doi     = {10.1523/jneurosci.3421-07.2007},
  pmid    = {17898224},
  url     = {https://doi.org/10.1523/jneurosci.3421-07.2007}
}

Key findings

• The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.

Why it matters

This cell study found that progranulin mediates cleavage of TDP-43 and that suppressing progranulin leads to caspase-dependent accumulation of TDP-43 fragments. It is an early cell-culture study and does not test any treatment or prevention for Alzheimer's disease, so it has no direct implications for treating, curing, or preventing the disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1523/jneurosci.3421-07.2007
• PubMed: 17898224
• Original source →
• Free full text: Journal of Neuroscience →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 Nature · 2006-07-16 · usefulness score 64/100 · Lewy body dementia
• Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 Nature · 2006-07-16 · usefulness score 61/100 · Lewy body dementia
• Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration Human molecular genetics · 2006-09-01 · usefulness score 59/100 · Lewy body dementia

Later studies that cite this one

30 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis PLoS genetics · 2008-09-19 · usefulness score 65/100 · Lewy body dementia
• TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics Neuron · 2017-08-01 · usefulness score 58/100 · Caregiving
• Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits Science (New York, N.Y.) · 2015-05-14 · usefulness score 57/100 · Lewy body dementia
• TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia The Lancet. Neurology · 2010-10-01 · usefulness score 57/100 · Lewy body dementia
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia
• Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue PloS one · 2010-10-11 · usefulness score 55/100 · Lewy body dementia
• Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity Proceedings of the National Academy of Sciences of the United States of America · 2009-04-21 · usefulness score 55/100 · Lewy body dementia
• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100 · Lewy body dementia

Related studies in Lewy body dementia

• Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation The Journal of biological chemistry · 2008-02-27 · usefulness score 53/100
• Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies Journal of neuropathology and experimental neurology · 2008-06-01 · usefulness score 51/100
• TAR DNA-binding protein 43 in neurodegenerative disease Nature reviews. Neurology · 2010-03-16 · usefulness score 49/100
• Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43 Proceedings of the National Academy of Sciences of the United States of America · 2012-08-29 · usefulness score 48/100
• Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic Cell reports · 2013-11-27 · usefulness score 55/100
• Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin Neuron · 2010-11-01 · usefulness score 53/100

Also tagged “tdp-43”

1,150 studies in the library carry the topic tag “tdp-43”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases The Journal of neuroscience : the official journal of the Society for Neuroscience · 2009-10-01 · usefulness score 52/100 · Lewy body dementia
• TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD Science (New York, N.Y.) · 2015-08-01 · usefulness score 57/100 · Lewy body dementia
• Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis Frontiers in Neuroscience · 2025-07-23 · usefulness score 38/100 · Brain tissue and pathology

Similar studies

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More on Lewy body dementia

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