Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration

Babu, Jeganathan Ramesh; Seibenhener, M. Lamar; Peng, Junmin; Ström, Anna-Lena; Kemppainen, Robert J.; Cox, Nancy R.; Zhu, Haining; Wooten, Michael C.; Diaz-Meco, Marı́a T.; Moscat, Jorge; Wooten, Marie W.

doi:10.1111/j.1471-4159.2008.05340.x

Cited by 221 publications

(123 citation statements)

References 62 publications

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“…Unlike previous reports of lower p62 expression in AD frontal cortex (95, 96), and enhanced tau phosphorylation in p62-deficient mice (97), we observed stable p62 protein levels in the hippocampus of MCI and early AD. Accumulation of p62 was described in NFTs in various neocortical areas from cases with a probable to definite diagnosis of AD (39, 40, 98).…”

Section: Discussioncontrasting

confidence: 99%

Hippocampal Endosomal, Lysosomal, and Autophagic Dysregulation in Mild Cognitive Impairment

Perez

Nadeem

et al. 2015

J Neuropathol Exp Neurol

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Endosomal-lysosomal and autophagic dysregulation occurs in the hippocampus in prodromal Alzheimer disease (AD), but its relationship with β-amyloid (Aβ) and tau pathology remain unclear. To investigate this issue, we performed immunoblot analysis of hippocampal homogenates from cases with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment (MCI) and AD. Western blot analysis revealed significant increases in the acid hydrolase cathepsin D (Cat D) and early endosome marker rabaptin5 in the MCI group compared to AD, whereas levels of phosphorylated mammalian target of rapamycin (mTOR) proteins, total mTOR, p62, traf6 and LilrB2 were comparable across clinical groups. Hippocampal Aβ1-40 and Aβ1-42 concentrations and AT8-immunopositive neurofibrillary tangle density were not significantly different across the clinical groups. Greater Cat D expression was associated with Global Cognitive Score and episodic memory score, but not with Mini Mental State Examination or advanced neuropathology criteria. These results indicate that alterations in hippocampal endosomal-lysosomal proteins in MCI are independent of tau or Aβ pathology.

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Section: Discussioncontrasting

confidence: 99%

Hippocampal Endosomal, Lysosomal, and Autophagic Dysregulation in Mild Cognitive Impairment

Perez

Nadeem

et al. 2015

J Neuropathol Exp Neurol

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“…Genetic ablation of p62 suppresses the formation of ubiquitin-positive protein aggregates in neurons [17]. p62 deficiency causes progressive loss of working memory and neurons in knockout mice [25]. Recent studies indicate that mutation of p62 is linked to ALS and FTLD [7, 27].…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Ubqln2 gains toxic properties to induce neuron death

Liu

Huang

et al. 2014

Acta Neuropathol

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Mutations in ubiquilin 2 (Ubqln2) is linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. A foremost question regarding Ubqln2 pathogenesis is whether pathogenically mutated Ubqln2 causes neuron death via a gain or loss of functions. To better understand Ubqln2 pathobiology, we created Ubqln2 transgenic and knockout rats and compared phenotypic expression in these novel rat models. Overexpression of Ubqln2 with a pathogenic mutation (P497H substitution) caused cognitive deficits and neuronal loss in transgenic rats at the age of 130 days. In the transgenic rats, neuronal loss was preceded by the progressive formation of Ubqln2 aggregates and was accompanied by the progressive accumulation of the autophagy substrates p62 and LC3-II and the impairment of endosome pathways. In contrast, none of these pathologies observed in mutant Ubqln2 transgenic rats was detected in Ubqln2 knockout rats at the age of 300 days. Together, our findings in Ubqln2 transgenic and knockout rats collectively suggest that pathogenic Ubqln2 causes neuron death mainly through a gain of unrevealed functions rather than a loss of physiological functions.

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“…1B). The PB1 domain is involved with p62’s role in activating NF-kB signaling[40, 41]. Since NF-kB activation generates inflammation during age-related diseases[42], including AMD[43-45], it is possible that suppression of isoform1 by isoform2 in RPE cells might be a response to prevent unwanted inflammation without interfering with Nrf2 signaling.…”

Section: Discussionmentioning

confidence: 99%

p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium

Wang¹,

Cano²,

Handa³

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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As a signaling hub, p62/sequestosome plays important roles in cell signaling and degradation of misfolded proteins. p62 has been implicated as an adaptor protein to mediate autophagic clearance of insoluble protein aggregates in age-related diseases, including age-related macular degeneration (AMD), which is characterized by dysfunction of the retinal pigment epithelium (RPE). Our previous studies have shown that cigarette smoke (CS) induces oxidative stress and inhibits the proteasome pathway in cultured human RPE cells, suggesting that p62-mediated autophagy may become the major route to remove impaired proteins under such circumstances. In the present studies, we found that all p62 mRNA variants are abundantly expressed and upregulated by CS induced stress in cultured human RPE cells, yet isoform1 is the major translated form. We also show that p62 silencing exacerbated the CS induced accumulation of damaged proteins, both by suppressing autophagy and by inhibiting the Nrf2 antioxidant response, which in turn, increased protein oxidation. These effects of CS and p62 reduction were further confirmed in mice exposed to CS. We found that over-expression of p62 isoform1, but not its S403A mutant, which lacks affinity for ubiquitinated proteins, reduced misfolded proteins, yet simultaneously promoted an Nrf2-mediated antioxidant response. Thus, p62 provides dual, reciprocal enhancing protection to RPE cells from environmental stress induced protein misfolding and aggregation, by facilitating autophagy and the Nrf2 mediated antioxidant response, which might be a potential therapeutic target against AMD.

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Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration

Cited by 221 publications

References 62 publications

Hippocampal Endosomal, Lysosomal, and Autophagic Dysregulation in Mild Cognitive Impairment

Hippocampal Endosomal, Lysosomal, and Autophagic Dysregulation in Mild Cognitive Impairment

Pathogenic Ubqln2 gains toxic properties to induce neuron death

p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium

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