Next-generation profiling to identify the molecular etiology of Parkinson dementia.

OBJECTIVE: We sought to determine the underlying cortical gene expression changes associated with Parkinson dementia using a next-generation RNA sequencing approach. METHODS: In this study, we used RNA sequencing to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex from neurologically normal control patients, patients with Parkinson disease, and patients with Parkinson disease with dementia. RESULTS: Genes overexpressed in both disease states were involved with an immune response, whereas shared underexpressed genes functioned in signal transduction or as components of the cytoskeleton. Alternative splicing analysis produced a pattern of immune and RNA-processing disturbances. CONCLUSIONS: Genes with the greatest degree of differential expression did not overlap with genes exhibiting significant alternative splicing activity. Such variation indicates the importance of broadening expression studies to include exon-level changes because there can be significant differential splicing activity with potential structural consequences, a subtlety that is not detected when examining differential gene expression alone, or is underrepresented with probe-limited array technology.

A generic research paradigm for identification and validation of early molecular diagnostics and new therapeutics in common disorders.

Genetically complex disorders continue to confound investigators because of their many underlying factors, both genetic and environmental. In order to tease apart the heritable from the non-heritable contributions to disease, clinicians are relying on researchers in the rapidly expanding fields of high-throughput genomics to identify surrogate clinical endpoints, called biomarkers, that provide a measure of the probability that an individual will succumb to the disease in question. The goals of current biomedical research into complex disorders are to identify and utilize these biomarkers, not only for early detection, but also for personalized treatment with knowledge-guided therapeutics. As the identification of these biomarkers is basically a problem of discovery, we discuss new insights into biomarker detection utilizing the most current genomic technologies available. Additionally, we present here a generic paradigm for the validation of such molecular diagnostics as well as new treatment modalities for complex and increasingly common diseases. Lastly, we delve into the ways genomic biomarkers might be implemented in a clinical setting to allow the subsequent application of targeted therapeutics, which can help the ever expanding groups of individuals experiencing these insidious diseases.

Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer's disease.

The role of iron metabolism in Alzheimer's disease (AD) is well documented. Regulation of the proteins that maintain cellular iron metabolism is mediated by two cytoplasmic RNA-binding proteins, the Iron Regulatory Proteins (IRP1 and IRP2), that function through post-transcriptional interactions with RNA stem loop structures called iron-responsive elements. As the primary mediator of iron homeostasis in neuronal cells, IRP2 is a strong candidate for polymorphisms that could impact AD pathogenesis. Thus, we performed a pilot study to assess polymorphisms in the gene encoding IRP2 (IREB2) on clinically well-characterized, post-mortem samples (50 AD and 50 controls). DNA sequence analysis of the IREB2 gene region revealed 14 polymorphisms. Two (rs2656070 and rs13180) showed statistically significant skewing of allelic and genotypic distributions between AD patients and controls. In silico analyses revealed that rs2656070 lies within a probable promoter and disrupts the binding sites of at least two known transcription factors. Though silent and likely not functionally relevant, rs13180 is in complete LD with rs2656070 (D' > 0.999), creating an IREB2-haplotype that is significantly associated with AD. Confirmation of this association in a larger cohort of cases and controls would further support the role of iron regulation in the pathogenesis of this catastrophic and increasingly common neurodegenerative disorder.