Localization and regional distribution of p23/TMP21 in the brain

Vetrivel, Kulandaivelu S.; Kodam, Anitha; Gong, Ping; Chen, Ying; Parent, Angèle; Kar, Satyabrata; Wang, Shuai

doi:10.1016/j.nbd.2008.06.012

Cited by 26 publications

(44 citation statements)

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“…In agreement, immunohistochemical analysis using a highly specific polyclonal p23 antibody [14] showed overall intense p23 staining in brain and spinal cord of Hup23 mice relative to non-transgenic (Ntg) littermates (Figure 1C). As we reported earlier, endogenous p23 is expressed mainly in neurons in rodent brain [14].…”

Section: Resultssupporting

confidence: 67%

Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice

Gong

Roseman

Fernandez

et al. 2011

Mol Neurodegeneration

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Backgroundp23 belongs to the highly conserved p24 family of type I transmembrane proteins, which participate in the bidirectional protein transport between the endoplasmic reticulum and Golgi apparatus. Mammalian p23 has been shown to interact with γ-secretase complex, and modulate secretory trafficking as well as intramembranous processing of amyloid precursor protein in cultured cells. Negative modulation of β-amyloid production by p23 in cultured cell lines suggested that elevation of p23 expression in neurons might mitigate cerebral amyloid burden.ResultsWe generated several lines of transgenic mice expressing human p23 in neurons under the control of Thy-1.2 promoter. We found that even a 50% increase in p23 levels in the central nervous system of mice causes post-natal growth retardation, severe neurological problems characterized by tremors, seizure, ataxia, and uncoordinated movements, and premature death. The severity of the phenotype closely correlated with the level of p23 overexpression in multiple transgenic lines. While the number and general morphology of neurons in Hup23 mice appeared to be normal throughout the brain, abnormal non-Golgi p23 localization was observed in a subset of neurons with high transgene expression in brainstem. Moreover, detailed immunofluorescence analysis revealed marked proliferation of astrocytes, activation of microglia, and thinning of myelinated bundles in brainstem of Hup23 mice.ConclusionsThese results demonstrate that proper level of p23 expression is critical for neuronal function, and perturbing p23 function by overexpression initiates a cascade of cellular reactions in brainstem that leads to severe motor deficits and other neurological problems, which culminate in premature death. The neurological phenotype observed in Hup23 mice highlights significant adverse effects associated with manipulating neuronal expression of p23, a previously described negative modulator of γ-secretase activity and β-amyloid production. Moreover, our report has broader relevance to molecular mechanisms in several neurodegenerative diseases as it highlights the inherent vulnerability of the early secretory pathway mechanisms that ensure proteostasis in neurons.

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Section: Resultssupporting

confidence: 67%

Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice

Gong

Roseman

Fernandez

et al. 2011

Mol Neurodegeneration

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“…Brains were cut sagitally in half, one hemisphere was fixed overnight in 4% paraformaldehyde at 4°C and then cryoprotected in PBS containing 30% sucrose. 30 μm sagittal sections were cut on a cryostat and processed following a free-floating procedure for either enzyme-linked immunoperoxidase or double immunofluorescence staining as described (Vetrivel et al, 2008). The following antibodies were used for immunohistochemistry: mouse monoclonal anti-Aβ1-5 (3D6, 83 ng/mL; Elan Pharmaceutical); polyclonal anti-nicastrin (SP718; 1:2000; (Kodam et al, 2008)); rabbit polyclonal antibody A2tag (1:4,000), which reacts with transgenic human APH1aL and endogenous mouse APH1 was raised against a synthetic peptide corresponding to the C-terminal 15 amino acids of APH1aL followed by residues SSRGPSSAEVLLLPVS; rat monoclonal anti-human PS1-NT antibody (1:500; generously provided by Allan Levey, Emory University), (Lah et al, 1997); monoclonal anti-phosphoneurofilament H antibody (1:500; SMI31, Sternberger Monoclonals/Covance); monoclonal anti-MAP2 (1:10,000; clone HM-2, ascites) and anti-synaptophysin (1:500, clone SVP-38, ascites) antibodies were both from Sigma; rabbit polyclonal antibody anti-Giantin (1:5000, PRB-114C, Covance).…”

Section: Methodsmentioning

confidence: 99%

Reduced Alzheimer's Disease β-Amyloid Deposition in Transgenic Mice ExpressingS-Palmitoylation-Deficient APH1aL and Nicastrin

Meckler¹,

Roseman²,

Das³

et al. 2010

J. Neurosci.

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Sequential cleavage of amyloid precursor protein by ␤-and ␥-secretases generates ␤-amyloid peptides (A␤), which accumulate in the brains of patients with Alzheimer's disease. We recently identified S-palmitoylation of two ␥-secretase subunits, APH1 and nicastrin. S-Palmitoylation is an essential posttranslational modification for the proper trafficking and function of many neuronal proteins. In cultured cell lines, lack of S-palmitoylation causes instability of nascent APH1 and nicastrin but does not affect ␥-secretase processing of amyloid precursor protein. To determine the importance of ␥-secretase S-palmitoylation for A␤ deposition in the brain, we generated transgenic mice coexpressing human wild-type or S-palmitoylation-deficient APH1aL and nicastrin in neurons in the forebrain. We found that lack of S-palmitoylation did not impair the ability of APH1aL and nicastrin to form enzymatically active protein complexes with endogenous presenilin 1 and PEN2 or affect the localization of ␥-secretase subunits in dendrites and axons of cortical neurons. When we crossed these mice with 85Dbo transgenic mice, which coexpress familial Alzheimer's disease-causing amyloid precursor protein and presenilin 1 variants, we found that coexpression of wild-type or mutant APH1aL and nicastrin led to marked stabilization of transgenic presenilin 1 in the brains of double-transgenic mice. Interestingly, we observed a moderate, but significant, reduction in amyloid deposits in the forebrain of mice expressing S-palmitoylation-deficient ␥-secretase subunits compared with mice overexpressing wild-type subunits, as well as a reduction in the levels of insoluble A␤ 40 -42 . These results indicate that ␥-secretase S-palmitoylation modulates A␤ deposition in the brain.

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“…In the context of AD, p23 has been found to bind γ-secretases and to promote the non-amyloidogenic pathway of amyloid precursor protein (ultimately reducing production of Aβ species; Vetrivel et al, 2008) and silencing of p23 gene expression reduced the levels of total tau and phosphorylated tau (Dickey et al, 2007). …”

Section: Hsp70/hsp90 Partners In Neurodegenerative Diseasesmentioning

confidence: 99%

The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases

et al. 2017

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The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD). Assembles of beta-amyloid (Aβ) peptide—either soluble (oligomers) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degradation, mostly by the proteasome. They form an important line of defense against misfolded proteins and are part of the cellular quality control system. The heat shock protein (Hsp) family, particularly Hsp70 and Hsp90, plays a major part in this process and it is well-known to regulate protein misfolding in a variety of diseases, including tau levels and toxicity in AD. However, the role of Hsp90 in regulating protein misfolding is not yet fully understood. For example, knockdown of Hsp90 and its co-chaperones in a Caenorhabditis elegans model of Aβ misfolding leads to increased toxicity. On the other hand, the use of Hsp90 inhibitors in AD mouse models reduces Aβ toxicity, and normalizes synaptic function. Stress-inducible phosphoprotein 1 (STI1), an intracellular co-chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly, STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In addition to its intracellular function, STI1 can be secreted by diverse cell types, including astrocytes and microglia and function as a neurotrophic ligand by triggering signaling via the cellular prion protein (PrPC). Extracellular STI1 can prevent Aβ toxic signaling by (i) interfering with Aβ binding to PrPC and (ii) triggering pro-survival signaling cascades. Interestingly, decreased levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In this review, we will discuss the role of intracellular and extracellular STI1 and the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in neurodegenerative diseases, with particular focus on AD.

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Localization and regional distribution of p23/TMP21 in the brain

Cited by 26 publications

References 29 publications

Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice

Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice

Reduced Alzheimer's Disease β-Amyloid Deposition in Transgenic Mice ExpressingS-Palmitoylation-Deficient APH1aL and Nicastrin

The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases

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