Influence of RNA-binding proteins on Alzheimer's disease and related cognitive endophenotypes

Introduction:

Malfunctioning RNA-binding proteins (RBP) have been linked to neurodegenerative diseases such as Alzheimer's disease (AD). It has been shown that genetic variations in RNA-binding proteins lead to alterations in RNA processing events and thus gene expression, thereby playing an important role in neurodegenerative processes. Moreover, it was observed that aggregated cytoplasmic RNA-protein complexes – consisting of RNA-binding proteins – accumulate in patients with AD and other neurodegenerative diseases.

Methods:

The present study investigated, if genetic polymorphisms in four differentially expressed RNA-binding proteins (HNRNPA2B1, HNRNPH3, ELAVL4 and PCBP2) identified to be differentially regulated in AD by an RNA expression array, are associated with AD and AD-related cognitive abilities in a German sample composed of 677 healthy controls and 323 patients with AD. 19 SNPs located in the above mentioned genes were clumped into 8 LD-independent regions. Logistic regression was used to compare cases and controls, linear regression to screen for an association with cognitive performance in the Mini Mental State Exam (MMSE) and the Boston Naming Test (BNT). Analyses were performed including age, gender, education, and ApoE status as covariates and clumped to 8 independent regions.

Results:

RNA expression of all 4 selected genes could be shown to be downregulated in AD. Suggestive associations (P < 0.05) of polymorphisms in the ELAVL4, HNRNPA2B1 and PCBP2 genes with AD as well as performance in the MMSE (ELAVL4), BNT (HNRNPA2B1) or both (PCBP2) could be identified. Carriers of genotypes more frequent in AD cases were associated with reduced cognitive performance.

Conclusion:

Our findings suggest that genetic polymorphisms in the RBP genes ELAVL4, HNRNPA2B1 and PCBP2 could be linked to AD as well as cognitive abilities. If the detected downregulation of their mRNA expression is influenced by the respective genotypes remains to be determined.