Baylor Research Institute

Noguchi, T., Y. Toiyama, T. Kitajima, H. Imaoka, J. Hiro, S. Saigusa, K. Tanaka, Y. Inoue, Y. Mohri, S. Toden and M. Kusunoki (2016). “Mirna-503 promotes tumor progression and is associated with early recurrence and poor prognosis in human colorectal cancer.” Oncology 90(4): 221-231.

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OBJECTIVES: MicroRNA (miR)-503 is downregulated in several cancers and plays a tumor-suppressive role in carcinogenesis. However, the miR-503 expression pattern, its clinical significance and its molecular mechanism in colorectal cancer (CRC) have not been investigated. METHODS: We analyzed miR-503 expression in normal mucosa (n = 20), adenoma (n = 27) and CRC (n = 20). We quantified miR-503 expression in an independent cohort (n = 191) and investigated the clinical significance of miR-503 in CRC. CRC cell lines were transfected with anti-miR-503 to assess its function and target gene. RESULTS: miR-503 expression increased according to the adenoma-carcinoma sequence. High miR-503 expression was significantly associated with large tumor size, serosal invasion, lymphatic and venous invasion as well as lymph node metastasis. CRC patients with high miR-503 expression had significantly earlier relapse and poorer prognosis than those with low expression. miR-503 was an independent recurrence marker in stage I/II CRC. In vitro, attenuated miR-503 expression resulted in inhibition of proliferation, invasion and migration and acquisition of anoikis of CRC cells. The putative target gene (calcium-sensing receptor) was significantly upregulated after miR-503 attenuation. CONCLUSIONS: miR-503 acts as an ‘onco-miR’ in CRC. High miR-503 expression is associated with early recurrence and poor prognosis in CRC.

Zhang, J., V. Lachance, A. Schaffner, X. Li, A. Fedick, L. E. Kaye, J. Liao, J. Rosenfeld, N. Yachelevich, M. L. Chu, W. G. Mitchell, R. G. Boles, E. Moran, M. Tokita, E. Gorman, K. Bagley, W. Zhang, F. Xia, M. Leduc, Y. Yang, C. Eng, L. J. Wong, R. Schiffmann, G. A. Diaz, R. Kornreich, R. Thummel, M. Wasserstein, Z. Yue and L. Edelmann (2016). “A founder mutation in vps11 causes an autosomal recessive leukoencephalopathy linked to autophagic defects.” PLoS Genet 12(4): e1005848.

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Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

Abdelwahab, M., D. Blankenship and R. Schiffmann (2016). “Long-term follow-up and sudden unexpected death in gaucher disease type 3 in egypt.” Neurol Genet 2(2): e55.

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OBJECTIVE: To describe the long-term follow-up and distinct phenotype of a large cohort of patients with Gaucher disease type 3 on enzyme replacement therapy (ERT) in Egypt. METHODS: A prospective cohort study of 78 patients on ERT who were followed for up to 9 years with yearly evaluations that included EEG and cognitive testing. RESULTS: Of the patients, 73% were homozygous for the L444P GBA1 mutation; all but 7 were neurologically symptomatic. Supranuclear gaze palsy with variable but stable cognitive function was present in 91% of patients. Convergent strabismus and bulbar dysfunction were noted in 22% and 37%, respectively. Features of oppositional defiant disorder were present in 54% of patients. Twenty-three patients (30%) developed seizures while on ERT for 1-9 years. Of those, 12 patients (15%) died suddenly and unexpectedly at a mean age of 6.7 +/- 5.0 years (range 1.5-18). Sudden death was usually associated with a seizure disorder or a terminal seizure, but 7 of 12 patients had a preceding normal EEG. An additional 11% had background slowing or epileptogenic activity on EEG without clinical seizures. There were 3 familial cases of sudden unexpected death. CONCLUSIONS: Despite having the most common GBA1 genotype known to be associated with neuronopathic Gaucher disease, patients with Gaucher disease type 3 in Egypt have a phenotype and a clinical outcome on ERT that are very different from those observed in other populations. Identifying putative modifying genes of this ethnic group is likely to lead to better therapy for neuronopathic Gaucher disease generally.

Mochel, F., E. Hainque, D. Gras, I. M. Adanyeguh, S. Caillet, B. Heron, A. Roubertie, E. Kaphan, R. Valabregue, D. Rinaldi, S. Vuillaumier, R. Schiffmann, C. Ottolenghi, J. Y. Hogrel, L. Servais and E. Roze (2016). “Triheptanoin dramatically reduces paroxysmal motor disorder in patients with glut1 deficiency.” J Neurol Neurosurg Psychiatry 87(5): 550-553.

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OBJECTIVE: On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. METHODS: We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. RESULTS: Patients with GLUT1-DS experienced a mean of 30.8 (+/-27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (+/-2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (+/-21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when triheptanoin was withdrawn. CONCLUSIONS: Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS.

Nicholls, R. E., J. M. Sontag, H. Zhang, A. Staniszewski, S. Yan, C. Y. Kim, M. Yim, C. M. Woodruff, E. Arning, B. Wasek, D. Yin, T. Bottiglieri, E. Sontag, E. R. Kandel and O. Arancio (2016). “PP2A methylation controls sensitivity and resistance to beta-amyloid-induced cognitive and electrophysiological impairments.” Proc Natl Acad Sci U S A 113(12): 3347-3352.

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Elevated levels of the beta-amyloid peptide (Abeta) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer’s disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Abeta exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Abeta-induced impairments. Neither transgene affected Abeta production or the electrophysiological response to low concentrations of Abeta, suggesting that these manipulations selectively affect the pathological response to elevated Abeta levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Abeta levels in AD patients.