Role of cpeb4 in huntington’s disease and in autism spectrum disorder

Resumen

Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor disturbance, cognitive decline and psychological dysfunction. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) are a family of proteins that regulate translation of specific mRNAs by modulating their poly(A) tail length. CPEBs participate in synaptic plasticity however their role in etiology of neurodegenerative diseases has not been studied. Based on different lines of evidence, we reasoned that altered CPEB function might contribute to HD. The first aim of this thesis was to explore the status of CPEBs in HD. We found CPEB1/CPEB4 imbalance in HD brain and an aberrant poly(A) tail length with concomitant alteration of their encoded protein levels. This alteration prominently affects HD-, Alzheimer’s- and Parkinson’s disease-related genes. Therefore, CPEB-dependent altered polyadenylation becomes a new molecular signature in neurodegeneration useful to identify novel effectors like the striatal atrophy-associated gene KTN1 whose decreased mRNA-adenylation and protein levels provide a possible explanation for HD preponderant striatal affectation. Strikingly, we noticed that high confidence autism spectrum disorder (ASD) risk genes were overrepresented among CPEB4 targets. This finding led us to hypothesize CPEB4 as a new hub in ASD gene expression. ASD is a neurodevelopmental disorder that manifests in childhood by impaired social communication and restrictive and repetitive behaviors. Genetic contribution to ASD resides on risk gene variants that are individually minimally penetrant. Since environmental factors also underlie idiopathic ASD, it is crucial to identify altered regulators able to orchestrate multiple ASD genes along neurodevelopment. Thereby, the second aim of this thesis was to study the status of CPEB4 in idiopathic ASD patients and to determinate its potential role in ASD risk gene regulation. We found that CPEB4 transcripts are mis-spliced in favor of the isoform lacking a neuronal-specific microexon in ASD brains. Then, genome-wide polyadenylation analysis revealed a new molecular signature of global poly(A) tail shortening with concomitant reduction of their protein levels that prominently affects high-confidence ASD genes. Equivalent CPEB4-selective splicing isoform-imbalance in mice is sufficient to mimic the mRNA polyadenylation and induces ASD-like neuroanatomical, electrophysiological and behavioral phenotypes. Collectively, these data support a key role of CPEB-mediated altered poly(A) in HD and across neurodegenerative diseases and unravel CPEB4 as a new node in ASD gene expression.