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Specific RNA splicing events tied to Alzheimer's disease progression

Results from a large-scale analysis published in Nature Genetics support dysregulation of messenger RNA splicing in the aging brain as a feature of Alzheimer’s disease.

Moreover, these aberrations may be genetically driven in some cases, according to the data.

“Mutations in RNA-binding proteins involved in splicing regulation and aberrant splicing have been linked to amyotrophic lateral sclerosis and autism,” Towfique Raj, PhD, assistant professor in the Ronald M. Loeb Center for Alzheimer's Disease at Mount Sinai, and colleagues wrote. “A comprehensive study of cis- and trans-acting genetic factors that regulate alternative splicing in aging brains is lacking.”

Using deep sequencing, researchers created a comprehensive genome-wide map of RNA splicing variation in the aging prefrontal cortex of 450 subjects post-mortem to identify abnormal mRNA splicing events related to Alzheimer’s disease. The investigators also generated a collection of splicing quantitative trait loci effects.

Raj and colleagues found that specific alternative splicing events linked to Alzheimer’s disease and that certain validated genetic associations affected splicing of a nearby gene because of the susceptibility allele.

Analysis revealed genetic variation affected splicing of 3,006 genes in the aging brain. The researchers found that abnormal splicing was the mechanism for the effects of the PICALM, CLU and PTK2B susceptibility alleles. Using a transcriptome-wide association sequencing approach to determine whether the effect of such variants in Alzheimer’s disease were mediated by altering splicing levels, the researchers identified 21 genes with significant links to Alzheimer’s disease. Many of these connections were observed in known loci, but eight were in novel loci (such as TBC1D7, AP2A1, AP2A2 and MAP1B).

"Most importantly, these new insights into genetic mechanisms in the aging brain will help offer new strategies and directions for RNA-targeted biomarkers and therapeutic intervention in Alzheimer's disease," Raj said in a press release.

The investigators concluded that these findings provide evidence of abnormal mRNA splicing in the aging brain as a feature of Alzheimer’s disease and that this was genetically driven in certain cases.

"Our transcriptome-wide reference map of RNA splicing in the aging cortex is a new resource that provides insights for many different neurologic and psychiatric diseases," Philip De Jager, MD, PhD, director for the Center of Translational and Computational Neuro-Immunology at Columbia University, said in the release. "For example, we define the mechanism for three of the genetic variants that contribute to Alzheimer's susceptibility. These variants change the proportion of different versions of the target Alzheimer's genes, resulting in altered cell function and, ultimately, the accumulation of neuropathology." – by Savannah Demko

Disclosure: The authors report no relevant financial disclosures.

Results from a large-scale analysis published in Nature Genetics support dysregulation of messenger RNA splicing in the aging brain as a feature of Alzheimer’s disease.

Moreover, these aberrations may be genetically driven in some cases, according to the data.

“Mutations in RNA-binding proteins involved in splicing regulation and aberrant splicing have been linked to amyotrophic lateral sclerosis and autism,” Towfique Raj, PhD, assistant professor in the Ronald M. Loeb Center for Alzheimer's Disease at Mount Sinai, and colleagues wrote. “A comprehensive study of cis- and trans-acting genetic factors that regulate alternative splicing in aging brains is lacking.”

Using deep sequencing, researchers created a comprehensive genome-wide map of RNA splicing variation in the aging prefrontal cortex of 450 subjects post-mortem to identify abnormal mRNA splicing events related to Alzheimer’s disease. The investigators also generated a collection of splicing quantitative trait loci effects.

Raj and colleagues found that specific alternative splicing events linked to Alzheimer’s disease and that certain validated genetic associations affected splicing of a nearby gene because of the susceptibility allele.

Analysis revealed genetic variation affected splicing of 3,006 genes in the aging brain. The researchers found that abnormal splicing was the mechanism for the effects of the PICALM, CLU and PTK2B susceptibility alleles. Using a transcriptome-wide association sequencing approach to determine whether the effect of such variants in Alzheimer’s disease were mediated by altering splicing levels, the researchers identified 21 genes with significant links to Alzheimer’s disease. Many of these connections were observed in known loci, but eight were in novel loci (such as TBC1D7, AP2A1, AP2A2 and MAP1B).

"Most importantly, these new insights into genetic mechanisms in the aging brain will help offer new strategies and directions for RNA-targeted biomarkers and therapeutic intervention in Alzheimer's disease," Raj said in a press release.

The investigators concluded that these findings provide evidence of abnormal mRNA splicing in the aging brain as a feature of Alzheimer’s disease and that this was genetically driven in certain cases.

"Our transcriptome-wide reference map of RNA splicing in the aging cortex is a new resource that provides insights for many different neurologic and psychiatric diseases," Philip De Jager, MD, PhD, director for the Center of Translational and Computational Neuro-Immunology at Columbia University, said in the release. "For example, we define the mechanism for three of the genetic variants that contribute to Alzheimer's susceptibility. These variants change the proportion of different versions of the target Alzheimer's genes, resulting in altered cell function and, ultimately, the accumulation of neuropathology." – by Savannah Demko

Disclosure: The authors report no relevant financial disclosures.