Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system

Wang, Xiaoju; Fan, Huadong; Ying, Zheng; Li, Bin; Wang, Hongfeng; Wang, Guanghui

doi:10.1016/j.neulet.2009.11.055

Cited by 179 publications

(130 citation statements)

References 21 publications

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“…In the present study, TDP-43 colocalized with p62 in the cytoplasm of neurons as well as the phosphorylated TDP-43 aggregate in the VPM/VPL were only observed in aged PGRN-deficient mice. Previous studies have shown that abnormal degradation by the autophagy-lysosomal pathway affects TDP-43 aggregation in the cytoplasm [29][30][31][32]. Taken together, these observations suggest that PGRN deficiency may be involved in generating TDP-43 aggregation in the cytoplasm associated with impaired cellular degradation by lysosomes.…”

Section: Discussionmentioning

confidence: 54%

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Tanaka

Chambers

Matsuwaki

et al. 2014

Acta Neuropathologica Communications

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Introduction: It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10-and 90-week-old wild-type and PGRN-deficient mice. Results: We showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-α and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice.

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Section: Discussionmentioning

confidence: 54%

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Tanaka

Chambers

Matsuwaki

et al. 2014

Acta Neuropathologica Communications

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“…Thus, the levels of the full-length TDP-43 and the 25 kDa and 35 kDa fragments would be higher without this autoregulatory scheme. Several papers have concluded that exogenous truncated TDP-43 fragments are more prone to degradation by UPS than the exogenous full-length TDP-43 protein (Caccamo et al, 2009;Pesiridis et al, 2011;Wang et al, 2010). However, alternative explanations could not previously be excluded.…”

Section: Discussionmentioning

confidence: 99%

“…To date, several studies have reported findings regarding the degradation of the TDP-43 protein. In particular, it has been found that overexpressed full-length TDP-43 protein and its truncated 25 kDa and 35 kDa fragments are degraded through both the ubiquitin proteasome system (UPS) (Kim et al, 2009;Urushitani et al, 2010;Wang et al, 2010) and macroautophagy pathways (Caccamo et al, 2009;Filimonenko et al, 2007;Ju et al, 2009;Wang et al, 2012). Most short-lived proteins are degraded by UPS through the 26S proteasome (DeMartino and Slaughter, 1999), whereas the autophagy-lysosomal pathway primarily catabolizes unnecessary organelles, long-lived proteins and misfolded and/or aggregated proteins (Ravikumar et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Metabolism and mis-metabolism of the neuropathological signature protein TDP-43

Huang

Bose

Majumder

et al. 2014

Journal of Cell Science

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BSTRACT TDP-43 (also known as TARDBP) is a pathological signature protein of neurodegenerative diseases, with TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD)-TDP and amyotrophic lateral sclerosis (ALS)-TDP. These TDP-43 proteinopathies are characterized by cytoplasmic insoluble TDP-43-positive aggregates in the diseased cells, the formation of which requires the seeding of TDP-25 fragment generated by caspase cleavage of TDP-43. We have investigated the metabolism and mis-metabolism of TDP-43 in cultured cells and found that endogenous and exogenously overexpressed TDP-43 is degraded not only by the ubiquitin proteasome system (UPS) and macroautophagy, but also by the chaperone-mediated autophagy (CMA) mediated through an interaction between Hsc70 (also known as HSPA8) and ubiquitylated TDP-43. Furthermore, proteolytic cleavage of TDP-43 by caspase(s) is a necessary intermediate step for degradation of the majority of the TDP-43 protein, with the TDP-25 and TDP-35 fragments being the main substrates. Finally, we have determined the threshold level of the TDP-25 fragment that is necessary for formation of the cytosolic TDP-43-positive aggregates in cells containing the full-length TDP-43 at an elevated level close to that found in patients with TDP-43 proteinopathies. A comprehensive model of the metabolism and mismetabolism of TDP-43 in relation to these findings is presented.

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“…As mentioned previously, inhibition of the autophagy compromises the ubiquitin-proteasome pathway (36,37). Evidence has been presented before that clearance of TDP-43 and its caspase-generated 35-and 25-kDa fragments is processed through both the autophagy (48 -50) as well as the proteasome pathway (48,49). For instance, use of the autophagy inhibitors such as 3-MA (49) and autophagy activators such as rapamycin (50) increases and reduces, respectively, the accumulation of TDP-43.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Autophagy by Neuropathological Protein TDP-43

Bose¹,

Huang²,

Shen

2011

Journal of Biological Chemistry

131

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TDP-43 (TAR DNA-binding protein) (1) is a highly conserved and abundantly expressed protein among the mammals and invertebrates (2, 3). The protein is located mainly in the nucleus as punctuated structures designated T-bodies (4), but it is also distributed in the cytoplasm as discrete RNA granules (5). Multiple cellular functions have been implicated to be regulated by TDP-43, which consist of but are not restricted to transcriptional repression, RNA processing including splicing, biogenesis of miRNAs, and even translation (reviewed in Refs. 6 -8). Some of these regulations have been shown to be mediated through the two RNA recognition motifs (RRM1 and RRM2) and the C-terminal glycine-rich, prion-like GQN domain (6, 7). Mutational studies have revealed that the RNA recognition motif 1 (RRM1) 3 domain contributes much of the nucleic acid binding activity, whereas the function of RRM2 is still unclear and appears to play a lesser role in RNA binding (7). Studies have also established that an intact GQN domain, which recruits additional heterogeneous ribonucleoprotein (hnRNPs), is also necessary for the splicing activity of TDP-43 (2, 9).More recently, TDP-43 has been identified as the major pathological signature protein of patients with the frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis (10, 11). In particular, the metabolism of TDP-43 in the diseased cells of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis are misregulated, resulting in the generation of polyubiquitinated, phosphorylated, and caspase-3-cleaved species concentrated in the ubiquitinated inclusions (UBIs) in the cytoplasm and, to a much lesser extent, in the nucleus. Often accompanied with formation of the cytoplasmic UBIs is depletion of the nuclear TDP-43 (10, 11) (reviewed in Ref. 12). A causative role of TDP-43 in the pathogenesis of these diseases is substantiated genetically by the identification of Ͼ30 different mutations in its C-terminal GQN domain (reviewed in Ref. 13). The molecular basis of misregulation of the TDP-43 metabolism remains to be examined. Also unclear are the exact roles of TDP-43 in the pathogenesis of diseases with TDP-43(ϩ)UBIs. Both loss-of-function of TDP-43 and gain-of-cytotoxicity, e.g. as caused by the TDP-43(ϩ)UBIs, have been suggested to facilitate the disease initiation as well as propagation (reviewed in Refs. 6,7,12,14).Regarding the scenario of pathogenesis by loss-of-function of TDP-43, it is interesting to note that knock-out of TDP-43 expression in mice and/or Drosophila could result in defects of early embryonic developments, impairment of the motor function, and decrease of learning ability (15-19). These studies, among others, have evidenced the importance of TDP-43 in development and/or neuronal function, but they do not provide clues to the role of this protein in TDP-43 proteinopathies on the molecular level. With respect to the metabolism of TDP-43, it is interesting to note that the homeo...

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Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system

Cited by 179 publications

References 21 publications

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Metabolism and mis-metabolism of the neuropathological signature protein TDP-43

Regulation of Autophagy by Neuropathological Protein TDP-43

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