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Jeremie Vitte

Jeremie Vitte, PhD
Senior Research Associate/Staff Scientist

House Research Institute
Dpt of Neural Tumor Research
2100 West Third Street
Los Angeles, CA 90057
Phone: (213) 989-6714
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Journal articles

Scott R Plotkin, Jaishri O Blakeley, D Gareth Evans, C Oliver Hanemann, Theo J M Hulsebos, Kim Hunter-Schaedle, Ganjam V Kalpana, Bruce Korf, Ludwine Messiaen, Laura Papi, Nancy Ratner, Larry S Sherman, Miriam J Smith, Anat O Stemmer-Rachamimov, Jeremie Vitte, Marco Giovannini (2013)  Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria.   American journal of medical genetics. Part A 161A: 3. 405-416 Mar  
Abstract: Schwannomatosis is the third major form of neurofibromatosis and is characterized by the development of multiple schwannomas in the absence of bilateral vestibular schwannomas. The 2011 Schwannomatosis Update was organized by the Children's Tumor Foundation ( and held in Los Angeles, CA, from June 5-8, 2011. This article summarizes the highlights presented at the Conference and represents the "state-of-the-field" in 2011. Genetic studies indicate that constitutional mutations in the SMARCB1 tumor suppressor gene occur in 40-50% of familial cases and in 8-10% of sporadic cases of schwannomatosis. Tumorigenesis is thought to occur through a four-hit, three-step model, beginning with a germline mutation in SMARCB1 (hit 1), followed by loss of a portion of chromosome 22 that contains the second SMARCB1 allele and one NF2 allele (hits 2 and 3), followed by mutation of the remaining wild-type NF2 allele (hit 4). Insights from research on HIV and pediatric rhabdoid tumors have shed light on potential molecular pathways that are dysregulated in schwannomatosis-related schwannomas. Mouse models of schwannomatosis have been developed and promise to further expand our understanding of tumorigenesis and the tumor microenvironment. Clinical reports have described the occurrence of intracranial meningiomas in schwannomatosis patients and in families with germline SMARCB1 mutations. The authors propose updated diagnostic criteria to incorporate new clinical and genetic findings since 2005. In the next 5 years, the authors expect that advances in basic research in the pathogenesis of schwannomatosis will lead toward clinical investigations of potential drug therapies.
Karo Tanaka, Ascia Eskin, Fabrice Chareyre, Walter J Jessen, Jan Manent, Michiko Niwa-Kawakita, Ruihong Chen, Cory H White, Jeremie Vitte, Zahara M Jaffer, Stanley F Nelson, Allan E Rubenstein, Marco Giovannini (2013)  Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2.   Clinical cancer research : an official journal of the American Association for Cancer Research 19: 14. 3856-3870 Jul  
Abstract: The growth and survival of neurofibromatosis type 2 (NF2)-deficient cells are enhanced by the activation of multiple signaling pathways including ErbBs/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The chaperone protein HSP90 is essential for the stabilization of these signaling molecules. The aim of the study was to characterize the effect of HSP90 inhibition in various NF2-deficient models.
Jérémie Vitte, Sabine Traver, André Maués De Paula, Suzanne Lesage, Giorgio Rovelli, Olga Corti, Charles Duyckaerts, Alexis Brice (2010)  Leucine-Rich Repeat Kinase 2 Is Associated With the Endoplasmic Reticulum in Dopaminergic Neurons and Accumulates in the Core of Lewy Bodies in Parkinson Disease.   J Neuropathol Exp Neurol 69: 9. 959-972 Sep  
Abstract: Mutation of the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequent genetic cause of Parkinson disease (PD). To understand the role of LRRK2 in the neuropathology of PD, we investigated the protein expression in a healthy brain and brains from patients with PD and its subcellular localization in dopaminergic neurons. LRRK2 was found to be widely expressed in healthy adult brain, including areas involved in PD. By double fluorescent staining, we found that endogenous LRRK2 is colocalized with the endoplasmic reticulum (ER) markers Neurotrace and KDEL in human dopaminergic neurons. Labeling of brain sections with anti-LRRK2 and anti-α-synuclein antibodies revealed localization of LRRK2 in the core of 24% of Lewybodies (LBs) in the substantia nigra and 11% of LBs in the locuscoeruleus in idiopathic PD patients. The percentage was increased to 50% in both areas in a patient with the G2019S LRRK2 mutation. The finding of ER localization suggests the possibility that LRRK2 is involved in the ER stress response and could account for the susceptibility to neuronal degeneration of LRRK2 mutation carriers. The localization of LRRK2 protein in the core of a subset of LBsdemonstrates the contribution of LRRK2 to LB formation and diseasepathogenesis.
Jérémie Vitte, Ruben Attali, Nasim Warwar, Irena Gurt, Judith Melki (2009)  Spinal muscular atrophy.   Adv Exp Med Biol 652: 237-246  
Abstract: Spinal muscular atrophies (SMA) are frequent autosomal recessive disorders characterized by degeneration of lower motor neurons. SMA are caused by mutations of the survival of motor neuron gene (SMN1) leading to a reduction of the SMN protein amount. The identification of SMN interacting proteins involved in the formation of the spliceosome and splicing changes in SMN-deficient tissues of mutant mice strongly support the view that SMN is involved in the splicing reaction. However, the molecular pathway linking SMN defect to the SMA phenotype remains unclear. From a better knowledge of the genetic basis of SMA and the defects resulting from the mutations of SMN1 in cellular or animal models, several therapeutics strategies have been selected aiming at targeting SMN2, a partially functional copy of SMN1 gene which remains present in patients, or to prevent neurons from death. Refined characterization of the degenerative process in SMA and the identification of the defective molecular pathway downstream from the SMN defect will provide further exciting insight into this disease in the near future. They should contribute to clarify the pathophysiology of SMA, the function of SMN and should help in designing potential targeted or non-targeted therapeutic molecules.
Margot Fournier, Jérémie Vitte, Jérôme Garrigue, Dominique Langui, Jean-Philippe Dullin, Françoise Saurini, Naïma Hanoun, Fernando Perez-Diaz, Fabien Cornilleau, Chantal Joubert, Héctor Ardila-Osorio, Sabine Traver, René Duchateau, Cécile Goujet-Zalc, Katerina Paleologou, Hilal A Lashuel, Christian Haass, Charles Duyckaerts, Charles Cohen-Salmon, Philipp J Kahle, Michel Hamon, Alexis Brice, Olga Corti (2009)  Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy.   PLoS One 4: 8. 08  
Abstract: In synucleinopathies, including Parkinson's disease, partially ubiquitylated alpha-synuclein species phosphorylated on serine 129 (P(S129)-alpha-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against alpha-synuclein-mediated toxicity in various models.We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and alpha-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of P(S129)-alpha-synuclein but not P(S87)-alpha-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the P(S129)-alpha-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with P(S129)-alpha-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin- and P(S129)-alpha-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of P(S129)-alpha-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human alpha-synuclein were significantly delayed in Parkin-deficient mice.These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.
Jérémie Vitte, Coralie Fassier, Francesco D Tiziano, Cécile Dalard, Sabrina Soave, Natacha Roblot, Christine Brahe, Pascale Saugier-Veber, Jean Paul Bonnefont, Judith Melki (2007)  Refined characterization of the expression and stability of the SMN gene products.   Am J Pathol 171: 4. 1269-1280 Oct  
Abstract: Spinal muscular atrophy (SMA) is characterized by degeneration of lower motor neurons and caused by mutations of the SMN1 gene. SMN1 is duplicated in a homologous gene called SMN2, which remains present in patients. SMN has an essential role in RNA metabolism, but its role in SMA pathogenesis remains unknown. Previous studies suggested that in neurons the protein lacking the C terminus (SMN(Delta7)), the major product of the SMN2 gene, had a dominant-negative effect. We generated antibodies specific to SMN(FL) or SMN(Delta7). In transfected cells, the stability of the SMN(Delta7) protein was regulated in a cell-dependent manner. Importantly, whatever the human tissues examined, SMN(Delta7) protein was undetectable because of the instability of the protein, thus excluding a dominant effect of SMN(Delta7) in SMA. A similar decreased level of SMN(FL) was observed in brain and spinal cord samples from human SMA, suggesting that SMN(FL) may have specific targets in motor neurons. Moreover, these data indicate that the vulnerability of motor neurons cannot simply be ascribed to the differential expression or a more dramatic reduction of SMN(FL) in spinal cord when compared with brain tissue. Improving the stability of SMN(Delta7) protein might be envisaged as a new therapeutic strategy in SMA.
Anne Tarrade, Coralie Fassier, Sabrina Courageot, Delphine Charvin, Jérémie Vitte, Leticia Peris, Alain Thorel, Etienne Mouisel, Nuria Fonknechten, Natacha Roblot, Danielle Seilhean, Andrée Diérich, Jean Jacques Hauw, Judith Melki (2006)  A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition.   Hum Mol Genet 15: 24. 3544-3558 Dec  
Abstract: Mutations of the spastin gene (Sp) are responsible for the most frequent autosomal dominant form of spastic paraplegia, a disease characterized by the degeneration of corticospinal tracts. We show that a deletion in the mouse Sp gene, generating a premature stop codon, is responsible for progressive axonal degeneration, restricted to the central nervous system, leading to a late and mild motor defect. The degenerative process is characterized by focal axonal swellings, associated with abnormal accumulation of organelles and cytoskeletal components. In culture, mutant cortical neurons showed normal viability and neurite density. However, they develop neurite swellings associated with focal impairment of retrograde transport. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules rich in detyrosinated alpha-tubulin and dynamic microtubules composed almost exclusively of tyrosinated alpha-tubulin. Here, we show that the Sp mutation has a major impact on neurite maintenance and transport both in vivo and in vitro. These results highlight the link between spastin and microtubule dynamics in axons, but not in other neuronal compartments. In addition, it is the first description of a human neurodegenerative disease which involves this specialized region of the axon.
Jérémie M Vitte, Bénédicte Davoult, Natacha Roblot, Michèle Mayer, Vandana Joshi, Sabrina Courageot, François Tronche, Jacqueline Vadrot, Marie Helene Moreau, François Kemeny, Judith Melki (2004)  Deletion of murine Smn exon 7 directed to liver leads to severe defect of liver development associated with iron overload.   Am J Pathol 165: 5. 1731-1741 Nov  
Abstract: Spinal muscular atrophy (SMA) is characterized by degeneration of lower motor neurons caused by mutations of the survival motor neuron 1 gene (SMN1). SMN is involved in various processes including the formation of the spliceosome, pre-mRNA splicing and transcription. To know whether SMN has an essential role in all mammalian cell types or an as yet unknown specific function in the neuromuscular system, deletion of murine Smn exon 7, the most frequent mutation found among SMA patients, has been restricted to liver. Homozygous mutation results in severe impairment of liver development associated with iron overload and lack of regeneration leading to dramatic liver atrophy and late embryonic lethality of mutant mice. These data strongly suggest an ubiquitous and essential role of full-length SMN protein in various mammalian cell types. In SMA patients, the residual amount of SMN allows normal function of various organs except motor neurons. However, data from mouse and human suggest that other tissues might be involved in severe form of SMA or during prolonged disease course which reinforce the need of therapeutic approaches targeted to all tissues. In addition, liver function of patients should be carefully investigated and followed up before and during therapeutic trials.
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