Cell-specific expression of the epm1 (cystatin B) gene in developing rat cerebellum

Riccio, Massimo; Santi, Spartaco; Dembić, Maja; Giaimo, Rossella Di; Cipollini, Elena; Costantino-Ceccarini, Elvira; Ambrosetti, Davide Carlo; Maraldi, N. M.; Melli, Marialuisa

doi:10.1016/j.nbd.2005.02.012

Cited by 23 publications

(37 citation statements)

References 40 publications

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“…In contrast, cystatin B expression was changed and paralleled decreased cathepsin B enzymatic activity. Gene deletion of cystatin B increased neuronal apoptosis in mice, demonstrating that cystatin B is important for neuronal survival (Brannvall et al 2003;Riccio et al 2005). The release of cathespin B may have consequences for neuronal loss by triggering apoptosis or by fueling inflammatory cascades.…”

Section: Discussionmentioning

confidence: 99%

Nitrated Alpha-Synuclein and Microglial Neuroregulatory Activities

Reynolds

Kadiu

Garg

et al. 2008

J Neuroimmune Pharmacol

114

100

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Microglial neuroinflammatory responses affect the onset and progression of Parkinson's disease (PD). We posit that such neuroinflammatory responses are, in part, mediated by microglial interactions with nitrated and aggregated alpha-synuclein (alpha-syn) released from Lewy bodies as a consequence of dopaminergic neuronal degeneration. As disease progresses, secretions from alpha-syn-activated microglia can engage neighboring glial cells in a cycle of autocrine and paracrine amplification of neurotoxic immune products. Such pathogenic processes affect the balance between a microglial neurotrophic and neurotoxic signature. We now report that microglia secrete both neurotoxic and neuroprotective factors after exposure to nitrated alpha-syn (N-alpha-syn). Proteomic (surface enhanced laser desorption-time of flight, 1D sodium dodecyl sulfate electrophoresis, and liquid chromatography-tandem mass spectrometry) and limited metabolomic profiling demonstrated that N-alpha-syn-activated microglia secrete inflammatory, regulatory, redox-active, enzymatic, and cytoskeletal proteins. Increased extracellular glutamate and cysteine and diminished intracellular glutathione and secreted exosomal proteins were also demonstrated. Increased redox-active proteins suggest regulatory microglial responses to N-alpha-syn. These were linked to discontinuous cystatin expression, cathepsin activity, and nuclear factor-kappa B activation. Inhibition of cathepsin B attenuated, in part, N-alpha-syn microglial neurotoxicity. These data support multifaceted microglia functions in PD-associated neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Nitrated Alpha-Synuclein and Microglial Neuroregulatory Activities

Reynolds

Kadiu

Garg

et al. 2008

J Neuroimmune Pharmacol

114

100

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“…Immunolabeling of BDNF or BDNF‐myc was performed as described previously (Riccio et al , 2005). Colocalization studies were performed by using antibodies recognizing EEA1, BiP, GM130 and NeuN proteins.…”

Section: Methodsmentioning

confidence: 99%

Hippocampal neurons recycle BDNF for activity-dependent secretion and LTP maintenance

Santi¹,

Cappello

Riccio³

et al. 2006

EMBO J

105

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Regulation of brain-derived neurotrophic factor (BDNF) secretion plays a critical role in long-term potentiation (LTP). It is generally thought that the supply for this secretion is newly synthesized BDNF targeted to the synapse. Here we provide evidence that hippocampal neurons additionally recycle BDNF for activity-dependent secretion. Exogenously applied BDNF is internalized by cultured neurons and rapidly becomes available for activity-dependent secretion, which is controlled by the same mechanisms that regulate the secretion of newly synthesized BDNF. Moreover, BDNF recycling replaced the new synthesis pathway in mediating the maintenance of LTP in hippocampal slices: the late phase LTP, which is abolished by protein synthesis inhibition, was rescued in slices preincubated with BDNF. Thus, endocytosed BDNF is fed back to the activity-dependent releasable pool required for LTP maintenance.

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“…It has been reported that stefin B can be found in both the cytosol and the nucleus (Riccio et al, 2005; Ceru et al, 2010b), although some authors (Kaur et al, 2010; Yang et al, 2011) did not observe nuclear staining. In a search for its nuclear function, in an astrocytoma cell line T98G stefin B was found to be expressed in the nucleus as well as in the cytosol.…”

Section: Progressive Myoclonus Epilepsy Of Type 1 (Epm1) As a Neurodementioning

confidence: 98%

“…Stefin B is not expressed in detectable amounts in the cerebellum, except in Purkinje cells of developing and adult rat brain (Riccio et al, 2005). Similarly, in human cerebellum, stefin B resides in Purkinje and Bergmann glial fibers and in the cerebral cortical neurons of the dentate gyrus of the hippocampus.…”

Section: Progressive Myoclonus Epilepsy Of Type 1 (Epm1) As a Neurodementioning

confidence: 99%

Human stefin B normal and patho-physiological role: molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants

Polajnar¹,

Čeru²,

Kopitar-Jerala³

et al. 2012

Front. Mol. Neurosci.

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Epilepsies are characterized by abnormal electrophysiological activity of the brain. Among various types of inherited epilepsies different epilepsy syndromes, among them progressive myoclonus epilepsies with features of ataxia and neurodegeneration, are counted. The progressive myoclonus epilepsy of type 1 (EPM1), also known as Unverricht-Lundborg disease presents with features of cerebellar atrophy and increased oxidative stress. It has been found that EPM1 is caused by mutations in human cystatin B gene (human stefin B). We first describe the role of protein aggregation in other neurodegenerative conditions. Protein aggregates appear intraneurally but are also excreted, such as is the case with senile plaques of amyloid-β (Aβ) that accumulate in the brain parenchyma and vessel walls. A common characteristic of such diseases is the change of the protein conformation toward β secondary structure that accounts for the strong tendency of such proteins to aggregate and form amyloid fibrils. Second, we describe the patho-physiology of EPM1 and the normal and aberrant roles of stefin B in a mouse model of the disease. Furthermore, we discuss how the increased protein aggregation observed with some of the mutants of human stefin B may relate to the neurodegeneration that occurs in rare EPM1 patients. Our hypothesis (Ceru et al., 2005) states that some of the EPM1 mutants of human stefin B may undergo aggregation in neural cells, thus gaining additional toxic function (apart from loss of normal function). Our in vitro experiments thus far have confirmed that four mutants undergo increased aggregation relative to the wild-type protein. It has been shown that the R68X mutant forms amyloid-fibrils very rapidly, even at neutral pH and forms perinuclear inclusions, whereas the G4R mutant exhibits a prolonged lag phase, during which the toxic prefibrillar aggregates accumulate and are scattered more diffusely over the cytoplasm. Initial experiments on the G50E and Q71P missense EPM1 mutants are described.

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Cell-specific expression of the epm1 (cystatin B) gene in developing rat cerebellum

Cited by 23 publications

References 40 publications

Nitrated Alpha-Synuclein and Microglial Neuroregulatory Activities

Nitrated Alpha-Synuclein and Microglial Neuroregulatory Activities

Hippocampal neurons recycle BDNF for activity-dependent secretion and LTP maintenance

Human stefin B normal and patho-physiological role: molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants

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