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Recent studies have shown that neuroglial progenitor/stem cells (NSCs) from different brain regions exhibit varying capacities for self-renewal and differentiation. In this study, we used neurofibromatosis-1 (NF1) as a model system to elucidate a novel molecular mechanism underlying brain region-specific NSC functional heterogeneity. We demonstrate that Nf1 loss leads to increased NSC proliferation and gliogenesis in the brainstem, but not in the cortex. Using Nf1 genetically engineered mice and derivative NSC neurosphere cultures, we show that this brain region-specific increase in NSC proliferation and gliogenesis results from selective Akt hyperactivation. The molecular basis for the increased brainstem-specific Akt activation in brainstem NSCs is the consequence of differential rictor expression, leading to region-specific mammalian target of rapamycin (mTOR)/rictor-mediated Akt phosphorylation and Akt-regulated p27 phosphorylation. Collectively, these findings establish mTOR/rictormediated Akt activation as a key driver of NSC proliferation and gliogenesis, and identify a unique mechanism for conferring brain region-specific responses to cancer-causing genetic changes.[Keywords: Neurofibromin; neural stem cell; regional heterogeneity; gliogenesis; Akt; mTOR] Supplemental material is available at http://www.genesdev.org. (Hitoshi et al. 2002). However, it is not known whether these intrinsic region-restricted NSC properties have relevance to human disease pathogenesis. While brain tumors can arise in any location in the CNS in adults, glial cell tumors (astrocytomas or gliomas) are most frequently observed in the cerebellum, brainstem (BS), and optic pathway/hypothalamus in children ). This anatomic predisposition is best illustrated by the neurofibromatosis-1 (NF1) inherited cancer syndrome, in which low-grade astrocytomas are located predominantly in the optic pathway/hypothalamus and BS of young children, with rare tumors developing in the cerebral cortex (Listernick et al. 1994;Pollack et al. 1996;Guillamo et al. 2003). In light of studies implicating cells with stem cell-like properties in the genesis of astrocytoma (for review, see Stiles and Rowitch 2008), it is conceivable that this regional distribution of tumors partly reflects the intrinsic heterogeneity of stem cells from different regions of the brain to expand in response to cancerassociated genetic changes. Based on the unique spatial distribution of gliomas in children with NF1, we chose to employ Nf1 genetically engineered mice and derivative NSCs to define the molecular basis for NSC heterogeneity in the brain.NF1 is the most common cancer predisposition syndrome in which affected children develop gliomas. NF1-associated gliomas result from biallelic inactivation of 3 Corresponding author. E-MAIL gutmannd@neuro.wustl.edu; FAX (314) 362-2388. Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi

Mouse models of human cancers afford unique opportunities to evaluate novel therapies in preclinical trials. For this purpose, we analyzed three genetically engineered mouse (GEM) models of low-grade glioma resulting from either inactivation of the neurofibromatosis-1 (Nf1) tumor suppressor gene or constitutive activation of KRas in glial cells. Based on tumor proliferation, location, and penetrance, we selected one of these Nf1 GEM models for preclinical drug evaluation. After detection of an optic glioma by manganese-enhanced magnetic resonance imaging, we randomized mice to either treatment or control groups. We first validated the Nf1 optic glioma model using conventional single-agent chemotherapy (temozolomide) currently used for children with low-grade glioma and showed that treatment resulted in decreased proliferation and increased apoptosis of tumor cells in vivo as well as reduced tumor volume. Because neurofibromin negatively regulates mammalian target of rapamycin (mTOR) signaling, we showed that pharmacologic mTOR inhibition in vivo led to decreased tumor cell proliferation in a dosedependent fashion associated with a decrease in tumor volume. Interestingly, no additive effect of combined rapamycin and temozolomide treatment was observed. Lastly, to determine the effect of these therapies on the normal brain, we showed that treatments that affect tumor cell proliferation or apoptosis did not have a significant effect on the proliferation of progenitor cells within brain germinal zones. Collectively, these findings suggest that this Nf1 optic glioma model may be a potential preclinical benchmark for identifying novel therapies that have a high likelihood of success in human clinical trials. [Cancer Res 2008;68(5):1520-8]

Numerous studies have suggested that astrocytes in the central nervous system (CNS) exhibit molecular and functional heterogeneity. In this regard, astrocytes from different CNS locations express distinct immune system and neurotransmitter proteins, have varying levels of gap junction coupling, and respond differently to injury. However, the relevance of these differences to human disease is unclear. Since brain tumors in children arise in specific CNS locations, we hypothesized that regional astrocyte heterogeneity might partly underlie the propensity for gliomas to arise in these areas. In this study, we performed high-density RNA microarray profiling on astrocytes from postnatal day 1 optic nerve, cerebellum, brainstem, and neocortex. We showed that astrocytes from each region are molecularly distinct, and we were able to develop gene expression patterns that distinguish astrocytes, but not neural stem cells, from these different brain regions. We next used these microarray data to determine whether brain tumor suppressor genes were differentially expressed in these distinct populations of astrocytes. Interestingly, neurofibromatosis type 1 (NF1) gene expression was decreased at both the RNA and protein levels in neocortical astrocytes relative to astrocytes from the other brain regions. To determine the functional significance of this finding, we found increased astrocyte proliferation in optic nerve, brainstem, and cerebellum, but not neocortex, following Nf1 inactivation in vitro and in vivo. These findings provide molecular evidence for CNS astrocyte heterogeneity, and suggest that differences in tumor suppressor gene expression might contribute to the regional localization of human brain tumors.

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The phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. © 2016 International Parkinson and Movement Disorder Society.

The INI1/SMARCB1 protein product (INI1), a component of a transcription complex, was recently implicated in the pathogenesis of schwannomas in two members of a single family with familial schwannomatosis 1 . Tumors were found to have both constitutional and somatic mutations of the SMARCB1 gene and showed a mosaic pattern of loss of INI1 expression by immunohistochemistry, suggesting a tumor composition of mixed null and haploinsufficient cells. To determine if this finding could be extended to all tumors arising in familial schwannomatosis, and how it compares to other multiple schwannoma syndromes (sporadic schwannomatosis and neurofibromatosis 2) as well as to sporadic, solitary schwannomas, we performed an immunohistochemistry analysis on 45 schwannomas from patients with multiple schwannoma syndromes and on 38 solitary, sporadic schwannomas from non-syndromic patients. A mosaic pattern of INI1 expression was seen in 93% of tumors from familial schwannomatosis patients, 55% of tumors from sporadic schwannomatosis, 83% of NF2-associated tumors and only 5% of solitary, sporadic schwannomas. These results confirm a role for INI1/SMARCB1 in multiple schwannoma syndromes and suggest that a different pathway of tumorigenesis occurs in solitary, sporadic tumors.The SMARCB1 (also known as INI1, hSNF5 and BAF47) is a tumor suppressor gene that maps to chromosome band 22q11.2. Biallelic inactivation of SMARCB1 is frequent in atypical teratoid/rhabdoid tumors (AT/RT) and malignant rhabdoid tumors, aggressive malignant tumors of the central nervous system and kidneys in children. Constitutional mutations of SMARCB1 can be seen in rare familial cases of AT/RT 2 . The protein encoded by SMARCB, the INI1 protein, is a subunit of the SWI/SNF ATP-dependent chromatin-remodeling complex and is ubiquitously expressed in all cell types examined 3 . AT/RT occurring both sporadically SMARCB1 lies in the candidate region for familial schwannomatosis, a form of neurofibromatosis characterized by multiple schwannomas without vestibular nerve involvement 5,6 . In a recent report 1 , constitutional and somatic mutations of the SMARCB1gene were found in tumors from a single kindred with familial schwannomatosis. Loss of nuclear INI1 protein expression by immunohistochemistry was seen in four separate tumors from two members of this family. However, in contrast to the immunostaining pattern of INI1 in AT/ RT, loss of INI1 expression was seen in only a subset of tumor cells suggesting a mosaic makeup of null and haploinsufficent cells. Furthermore, several previous studies have identified somatically acquired mutations in the NF2 gene in schwannomatosis tumors 6 ,, 7 , but in tumors from this family no molecular evidence of NF2 involvement was seen, raising the question of how representative this family may be. Here we report an expansion of these results to other familial schwannomatosis kindreds as well as analysis of the INI expression pattern in tumors associated with other multiple schwannoma syndromes (sporadic schwannomatos...

Mutations of PLA2G6 gene have been lately proposed to be the causative gene for PARK14 in patients with autosomal recessive young-onset parkinsonism (YOPD). The role of PLA2G6 mutations as a risk factor for Parkinson's disease is not clear. To study the PLA2G6 mutations in PARK14-linked patients and its association with the onset of sporadic Parkinson's disease (sPD), sequencing and gene dosage analyses were carried out in 25 patients (onset age ≦30 years) then the identified variants were assessed in 956 sporadic PD (sPD) patients and 802 age-matched healthy controls. Four genetic variants were identified; one patient had homozygous c.991G > T (p.Asp331Tyr) mutation, two had compound heterozygous c.991G > T/c.1077G > A (p.Met358IlefsX) mutation, one had single c.1976A > G (p.Asn659Ser) mutation, and one patient had an exon 1 hetero-deletion. The c.1077G > A mutation resulted in a 4-bp deletion in leukocyte mRNA by activating a cryptic splice site in exon 7. Only p.Asp331Tyr was identified in four sPD patients and four controls. The onset age for PLA2G6 mutation carriers was younger than that for sPD (29.86 ± 8.59 vs. 56.84 ± 11.33 years, P = 0.0002). The analysis of previously reported PARK14 patients revealed that those who carried a truncated mutation tended to have a complicated phenotype and atrophies of cortex and cerebellum. In conclusion, PLA2G6 mutation was the second common genetic cause after PRKN mutation in our YOPD patients and might be a risk factor for early-onset PD in Han Chinese. Additionally, mutation data should be interpreted carefully because even a synonymous mutation could cause abnormal mRNA splicing.