Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.

Huntington's disease (HD) is a devastating hereditary neurodegenerative disorder of the basal ganglia for which disease-modifying treatments are not available. Although promising genesilencing therapies are currently being tested, new molecular mechanisms underneath the triggering mutation must be explored to identify easily druggable targets. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) are RNA-binding proteins that repress or activate translation of CPE-containing transcripts by, respectively, shortening or elongating their poly(A) tail. Here we report increased CPEB1 and decreased CPEB4 protein levels in striatum of HD patients and mouse models. This correlates with a reprogramming of polyadenylation in 17.3% of the transcriptome that markedly affects neurodegeneration-associated genes (like PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS and HTT), thus suggesting a new molecular mechanism in neurodegenerative disease aetiology. Besides, we found decreased protein levels of top deadenylated transcript-genes which include striatal atrophy-linked genes not previously related to HD such as KTN1 and, remarkably, the easily druggable SLC19A3 (ThTr2 thiamine transporter). Mutations in SLC19A3 cause biotin-thiamine-responsive basal ganglia disease (BTBGD), a devastating striatal disorder that however reverts upon a vitaminbased therapy. Decreased ThTr2 in HD led to discover that, alike BTBGD patients, HD patients show decreased CSF thiamine levels. Furthermore, HD patients and mice show decreased striatal concentrations of TPP, the metabolically active form of thiamine. Remarkably, a high dose biotin+thiamine treatment used to revert BTBGD prevented the TPP deficiency of HD mice and attenuated their radiological, neuropathological and motor HD-like phenotypes, thus unveiling an easy to implement therapy for HD.