Chiesa R, Piccardo P, Dossena S, Nowoslawski L, Roth KA, Ghetti B et al.. Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease. Proc Natl Acad Sci USA 102: 238-243

Dulbecco Telethon Institute and Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2005; 102(1):238-43. DOI: 10.1073/pnas.0406173102
Source: PubMed


Transgenic Tg(PG14) mice express a mutant prion protein containing 14 octapeptide repeats, whose human homologue is associated with an inherited prion dementia. These mice develop a progressive neurological disorder characterized by ataxia and cerebellar atrophy, with massive apoptotic degeneration of granule neurons. Bax, a proapoptotic gene of the Bcl-2 family, plays a key role in regulating cell death in the nervous system. To analyze the role of Bax in the Tg(PG14) phenotype, we crossed Tg(PG14) mice with Bax(-/-) mice to obtain Tg(PG14)/Bax(-/-) offspring. Bax deletion effectively rescued cerebellar granule neurons from apoptosis, implying that these cells die via a Bax-dependent process. Surprisingly, however, the age at which symptoms began and the duration of the clinical phase of the illness were not altered in Tg(PG14)/Bax(-/-) mice. In addition, Bax deletion failed to prevent shrinkage of the molecular layer of the cerebellum and loss of synaptophysin-positive synaptic endings. Our analysis indicates that synaptic loss makes a critical contribution to the Tg(PG14) phenotype. These results provide insights into the pathogenesis of prion diseases and have important implications for the treatment of these disorders.

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    • "Abnormal expression of amyloid beta precursor protein in Alzheimer's disease and mutation of huntingtin protein in Huntington's disease contributes toward the accumulation of protein aggregates that block the axonal transport and causes swelling of axons (Li et al. 2001; Gunawardena et al. 2003; Stokin et al. 2005). Early stages of sporadic and inherited forms of prion disease as well as the acquired form of transmitted prion disease also show impaired axonal transport and synaptic anomalies (Clinton et al. 1993; Cunningham et al. 2003; Chiesa et al. 2005). Endoplasmic reticulum plays key role in neuronal cell death through chaperones . "
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    ABSTRACT: Dysregulated calcium signaling and accumulation of aberrant proteins causing endoplasmic reticulum stress are the early sign of intra-axonal pathological events in many neurodegenerative diseases, and apoptotic signaling is initiated when the stress goes beyond the maximum threshold level of endoplasmic reticulum. The fate of the cell to undergo apoptosis is controlled by Ca2(+) signaling and dynamics at the level of the endoplasmic reticulum. Endoplasmic reticulum resident inositol 1,4,5-trisphosphate receptors (IP3R) play a pivotal role in cell death signaling by mediating Ca2(+) flux from the endoplasmic reticulum into the cytosol and mitochondria. Hence, many prosurvival and prodeath signaling pathways and proteins affect Ca2(+) signaling by directly targeting IP3R channels, which can happen in an IP3R-isoform-dependent manner. Here, in this review, we summarize the regulatory mechanisms of inositol triphosphate receptors in calcium regulation and initiation of apoptosis during unfolded protein response.
    Full-text · Article · Apr 2015 · Journal of Molecular Neuroscience
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    • "To test whether blocking the apoptotic program could prevent neurodegeneration and motor dysfunction, we crossed Tg(PG14) with Bax knockout mice. Bax deletion efficiently rescued CGNs but had no effect on the development of ataxia and synaptic loss [53]. This suggested that disruption of synaptic connectivity in the cerebellum was vital in the Tg(PG14) disease and prompted us to test whether abnormalities in neurotransmission could be detected before neurodegeneration, in parallel with the onset of motor dysfunction. "
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    ABSTRACT: Synaptic dysfunction is an important cause of neurological symptoms in prion diseases, a class of clinically heterogeneous neurodegenerative disorders caused by misfolding of the cellular prion protein (PrP(C)). Experimental data suggest that accumulation of misfolded PrP(C) in the endoplasmic reticulum (ER) may be crucial in synaptic failure, possibly because of the activation of the translational repression pathway of the unfolded protein response. Here, we report that this pathway is not operative in mouse models of genetic prion disease, consistent with our previous observation that ER stress is not involved. Building on our recent finding that ER retention of mutant PrP(C) impairs the secretory trafficking of calcium channels essential for synaptic function, we propose a model of pathogenicity in which intracellular retention of misfolded PrP(C) results in loss of function or gain of toxicity of PrP(C)-interacting proteins. This neurotoxic modality may also explain the phenotypic heterogeneity of prion diseases.
    Full-text · Article · Nov 2013 · International Journal of Cell Biology
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    • "the Tg(PG14) transgenic mice that express a mutant PrP with 14 octapeptide repeats [37] and present a progressive neurological disorder with ataxia, PrP deposition, and massive loss of cerebellar granule cells. They also display the main biochemical properties of PrPSc, such as partial resistance to proteinase K, detergent insolubility and resistance to GPI-anchor cleavage by phospholipase; "
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    ABSTRACT: Prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. In humans, Creutzfeldt-Jakob disease is the most studied prion disease. In animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in North America. The hallmark of prion diseases is the deposition in the brain of PrP(Sc), an abnormal β -sheet-rich form of the cellular prion protein (PrP(C)) (Prusiner 1982). According to the prion hypothesis, PrP(Sc) can trigger the autocatalytic conversion of PrP(C) into PrP(Sc), presumably in the presence of cofactors (lipids and small RNAs) that have been recently identified. In this review, we will come back to the original works that led to the discovery of prions and to the protein-only hypothesis proposed by Dr. Prusiner. We will then describe the recent reports on mammalian synthetic prions and recombinant prions that strongly support the protein-only hypothesis. The new concept of "deformed templating" regarding a new mechanism of PrP(Sc) formation and replication will be exposed. The review will end with a chapter on the prion-like propagation of other neurodegenerative disorders, such as Alzheimer's and Parkinson's disease and tauopathies.
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