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August 2011.

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Mining the autistic brain transcriptome
Voineagu and colleagues analyzed microarray data obtained using
post mortem brain tissue from autism cases and controls. Reproducible, disease-specific gene expression signatures were identified
in the cortex, but not in specimens from the superior temporal
gyrus or cerebellum. Next, the authors applied a weighted coexpression network-based analysis to integrate the detected gene
expression differences into a systems level context, and observed
that the regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly reduced in the
autistic brain, suggesting abnormalities in cortical patterning. Furthermore, the analysis identified discrete modules of co-expressed
genes previously reported to be associated with autism susceptibility, including the neuronal specific splicing factor A2BP1 (also
known as FOX1), supporting the genetic basis of synaptic and neuronal signaling dysfunction in autism. In addition, multiple A2BP1
predicted targets showed evidence of alternative splicing events. A
module enriched for immune genes and glial markers was also
prominent. However, since these are not typically found in genetic
association studies, the authors speculate that immune dysregulation is secondary and related to abnormal ongoing plasticity in the
autistic brain. Altogether, the study shows the convergence of
genomic and trascriptomic molecular abnormalities operating in
autism, and provides an experimental paradigm to study other neurodevelopmental disorders including schizophrenia and attention
deficit disorders (Nature 2011, 474:380-384).
A really interesting new gene for Moyamoya disease
Moyamoya disease (MMD) is a multifactorial progressive occlusive
disease of the cerebral vasculature. Children under 10 years of age
account for nearly 50% of all MMD cases and family history of
the disease is reported by approximately 15% of affected individuals. To identify genomic variants associated with MMD, Kamada
and co-workers performed a genome wide association study
(GWAS) that yielded a remarkable strong association signal in
chromosome 17q25 despite the relatively small number of cases
(N�) and controls (N�) included in the experiment (P < 108
). Additional fine mapping of this region of interest identified a
risk haplotype at the RNF213 locus, which codes for a Ring Finger
protein highly expressed in the spleen and lymphocytes. The high
expression of RNF213 in lymphocytes compared to brain may be
indicative of a role for these cells in the pathogenesis of MMD.
Sequencing analysis of RNF213 revealed a possible founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial
MMD cases and 1.4% of controls, providing an explanation for
the disproportional high disease frequency in Japanese. This mutation increases substantially the risk of MMD (odds ratio � 190.8
in this study). The strong statistical association values and conferred
risk, together with complete segregation in families lead the authors
to suggest the potential for pre-symptomatic diagnosis or exclusion
though genetic testing (J Hum Genet 2011, 56:334-341).
Triplet repeats can disturb transcription
Most RNA transcripts are noncoding and could contribute to the
pathogenesis of disease through their effects on the expression of coding sequences. Spinocerebellar ataxia type 7 (SCA7), also known as
autosomal dominant cerebellar ataxia type 2 (ADCA2) or ataxia with
pigmentary retinopathy, is a neurodegenerative disorder caused by a
CAG polyglutamine repeat expansion in exon 2 of the ATXN7 gene.
Ataxin-7 is a component of two transcription co-activator complexes
and is presumed to regulate the expression of several genes. Sopher
and colleagues examined regulation of ATXN7 to understand the
pathogenesis of SCA7. They found that the repeat and translation
initiation sites are flanked by binding sites for the transcriptional regulator CTCF and that this region also contains a convergently transcribed antisense noncoding RNA, which the authors named
SCAANT1 (spinocerebellar ataxia-7 antisense noncoding transcript
1). Using promoter analysis, transgenic mice expressing ataxin-7 minigenes, and fibroblasts from patients, they found that CTCF binding
is required for SCAANT1 expression and that SCAANT1 expression
is reduced by the expanded repeat in exon 2. Reduction of
SCAANT1 expression de-repressed ataxin-7 sense transcription and
was associated with local chromatin remodeling that favored high levels of ataxin-7 expression and appearance of a neurological disorder
in mice characterized by retinal and spinocerebellar degeneration.
Prior work in the field has suggested that the major factor in the
pathogenesis of repeat diseases is transition of the polyglutamine
expansion to an altered protein conformation. This study of SCA7,
however, demonstrates an important role for repeat-induced disruption of transcription, leading to overexpression of ataxin-7. Disturbances in transcription of noncoding regulatory RNAs may contribute to
the pathogenesis of other repeat diseases and may help explain the
cell-type specificity and distinct patterns of neuropathology in these
diseases. (Neuron 2011, 70:1071-1084).
A Gaucher-Parkinson duet
The synaptic protein a-synuclein is thought to play a major role in
the pathogenesis of Parkinson?s disease because it is a key component
of Lewy bodies, and variations in its gene, SNCA, are associated with
inherited and sporadic forms of the disease. There is intense interest
in discovering mechanisms by which a-synuclein promotes neurodegeneration. Gaucher?s disease is a lysosomal storage disorder due to
loss-of-function mutations in the gene GBA, which encodes glucocerebrosidase (GCase). Following up on findings that patients and family members carrying Gaucher?s mutations are at high risk for Parkinson?s disease, Mazzulli and colleagues studied the relationship between
GCase and a-synuclein. They found that knockdown of GCase
results in accumulation of glucocerebroside, which decreases lysosomal turnover preferentially affecting a-synuclein and stabilizes high
molecular oligomers of a-synuclein. Similar results were detected in
neurons reprogrammed from pluripotent stem cells harboring loss-offunction mutations in GCase. GCase deficiency also produced neurotoxocity that was dependent on the ability of a-synuclein to aggregate
since it did not occur in cells that expressed an a-synuclein mutant
lacking a domain important for aggregation. Conversely, increases in
a-synuclein impaired GCase function by impairing its trafficking to
lysosomes. These findings identify a positive feedback loop whereby
elevated levels of a-synuclein deplete lysosomal GCase and increase
levels of a-synuclein oligomers through accumulation of glucocerebroside. The authors propose that this positive feedback process proceeds
until a pathogenic threshold is surpassed, resulting in disease. If true,
then strategies that restore GCase function in lysosomes may prevent
progression of Parkinson?s disease (Cell 2011, 146: 37-52).
C 2011 American Neurological Association
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