Accumulation of protease-resistant prion protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation

Chiesa, Roberto; Drisaldi, Bettina; Quaglio, Elena; Migheli, Antonio; Piccardo, Pedro; Ghetti, Bernardino; Harris, David A.

doi:10.1073/pnas.97.10.5574

Cited by 139 publications

(130 citation statements)

References 30 publications

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“…Ataxia and CGN loss are seen in many patients with prion disease (Collinge et al ., 1992; Faucheux et al ., 2011) and in transgenic mice expressing a prion protein insertional mutation (Chiesa et al ., 2000). Muzaimi et al .…”

Section: Discussionmentioning

confidence: 99%

“…In Cockayne syndrome, a human hereditary DNA repair disorder, CGNs degenerate and are reduced in number (Kohji et al ., 1998). CGN loss also occurs in many prion disease cases (Collinge et al ., 1992; Faucheux et al ., 2011) and in transgenic mice expressing a prion protein with insertional mutation (Chiesa et al ., 2000). Many drugs are associated with drug‐induced cerebellar ataxia (van Gaalen et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

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The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Liu

Lü

2015

Aging Cell

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SummaryReactive oxygen species are implicated in age‐associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2‐like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age‐associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria‐targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age‐matched normal control mice or SkQ1‐treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4‐hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age‐associated neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Liu

Lü

2015

Aging Cell

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“…Finally, an octarepeat expansion familial prion disease allele (octa13) comprised a third internal control. This was pro-apoptotic to an equal or greater extent as Dpl but insensitive to the presence of wt Prnp alleles, as is indeed the case for expression of an octa14 allele ("PG14") assayed in Tg mice (49). A practical consequence of these findings is that it may be possible to While results of our genetic assays are in close accord with in vivo paradigms, we failed to establish a parallel assay based upon treatment of cerebellar cells with natively folded recombinant Dpl and PrP (prepared as described previously (13, 54)).…”

Section: A Cellular Assay For Prnp/prnd Interactionsmentioning

confidence: 95%

“…These alleles behave as dominant traits and, unlike the situation for Dpl, do not behave differently when expressed in the presence or absence of endogenous mouse Prnp alleles (49). The mutant PRNP allele (encoding an additional eight octarepeats above the five present in wt PRNP alleles) used for this experiment was derived from a Gerstmann-Strä ussler Scheinker patient (50).…”

Section: Resultsmentioning

confidence: 99%

Genetic Mapping of Activity Determinants within Cellular Prion Proteins

Drisaldi

Coomaraswamy

Mastrangelo

et al. 2004

Journal of Biological Chemistry

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The PrP-like Doppel (Dpl) protein causes apoptotic death of cerebellar neurons in transgenic mice, a process prevented by expression of the wild type (wt) cellular prion protein, PrP C . Internally deleted forms of PrP C resembling Dpl such as PrP⌬32-121 produce a similar PrP C -sensitive pro-apoptotic phenotype in transgenic mice. Here we demonstrate that these phenotypic attributes of wt Dpl, wt PrP C , and PrP⌬132-121 can be accurately recapitulated by transfected mouse cerebellar granule cell cultures. This system was then explored by mutagenesis of the co-expressed prion proteins to reveal functional determinants. By this means, neuroprotective activity of wt PrP C was shown to be nullified by a deletion of the N-terminal charged region implicated in endocytosis and retrograde axonal transport (PrP⌬23-28), by deletion of all five octarepeats (PrP⌬51-90), or by glycine replacement of four octarepeat histidine residues required for selective binding of copper ions (Prnp"H/G"). In the case of Dpl, overlapping deletions defined a requirement for the gene interval encoding helices B and B (Dpl⌬101-125). These data suggest contributions of copper binding and neuronal trafficking to wt PrP C function in vivo and place constraints upon current hypotheses to explain Dpl/PrP C antagonism by competitive ligand binding. Further implementation of this assay should provide a fuller understanding of the attributes and subcellular localizations required for activity of these enigmatic proteins.

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“…3) represent the Cu-Ai, where Ai are the atoms of the first shell. The three-body and four-body signals are called ␥ (3) and ␥ (4) functions. The three-body ␥ (3) is the sum of the signal due to the Cu-A-B triple scattering process plus the Cu-B two-body signal.…”

mentioning

confidence: 99%

Inter- and Intra-octarepeat Cu(II) Site Geometries in the Prion Protein

Morante

González-Iglesias

Potrich

et al. 2004

Journal of Biological Chemistry

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Cu(II) binding to the ␣ prion protein (␣PrP) can be both intramolecular and intermolecular. X-ray absorption spectroscopy at the copper K-edge has been used to explore the site geometry under each binding mode using both insoluble polymeric Cu(II)⅐␣BoPrP-(24 -242) (bovine PrP) complexes and soluble Cu(II) complexes of peptides containing one, two, and four copies of the octarepeat. Analysis of the extended region of the spectra using a multiple scattering approach revealed two types of sites differing in the number of His residues in the first coordination shell of Cu(II). Peptides containing one and two-octarepeat copies in sub-stoichiometric Cu(II) complexes showed the direct binding of a single His in accord with crystallographic intra-repeat geometry. Alternatively, the polymeric Cu(II)⅐␣BoPrP-(24 -242) complex and Cu(II) in its soluble complex with a fouroctarepeat peptide at half-site-occupancy showed Cu(II) directly bound to two His residues, consistent with an inter-repeat binding mode. Increasing the Cu(II) site occupancy from 0.5 to 0.75 in the peptide containing four octarepeats resulted in spectral features that are intermediate to those of the inter-and intra-repeat modes. The transition from His-Cu-His (inter-repeat) to Cu-His (intra-repeat) on increasing Cu(II) saturation offers a structural basis for the positive cooperativity of the cation binding process and explains the capacity of ␣PrP to participate in Cu(II)-mediated intermolecular interactions.PrP C , 1 a two-domain protein, has become a key molecule for understanding the group of lethal neurodegenerative disorders known as prion diseases (1). These disorders are characterized by the over-stabilization of alternative conformers (PrP Sc ) of the cellular prion protein with acquired self-perpetuating properties (1-3). Even though the structural changes occur at the C-terminal domain, the N-terminal region plays a regulatory role in the overall process leading to the conversion of PrP C into PrP Sc (4 -7). Among the different functions attributed to PrP C , Cu(II) interaction is, to date, the only one that has been correlated with physiological impairments linked to the disease (8).Cu(II) interaction was first described in the protocol tailored for PrP C purification and attributed to the His residues of the N-terminal domain (9 -19). These residues are located within the tandemly repeated PHGGGWGQ sequence known as the octarepeat and at the flexible hinge that connects the N-terminal and C-terminal domains (16 -20). In addition to these, other minor Cu(II)-binding sites in the C-terminal globular domain have been reported (19,21,22). Studies with PrP C models, as synthetic peptides and recombinant forms, have shown binding stoichiometries of up to one Cu(II) per octarepeat motive in a process in which the interaction among cation sites, measured as positive cooperativity, appears when the number of sites is higher than two (15,18,(22)(23)(24). The binding affinity constants varied in the femto to micromolar range and show strong pH dependenc...

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Accumulation of protease-resistant prion protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation

Cited by 139 publications

References 30 publications

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Genetic Mapping of Activity Determinants within Cellular Prion Proteins

Inter- and Intra-octarepeat Cu(II) Site Geometries in the Prion Protein

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