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Neuronal expression of Alzheimer's disease-associated U1-70K cleavage product causes splicing dysfunction and cognitive impairment in mice

ABSTRACT: Alzheimer's disease (AD) displays progressive cognitive decline that is associated with protein ß-amyloid and tau aggregation, but the causative mechanisms are not fully understood. Recent proteomics profiling has identified, in sporadic and familial cases, a tangle-like pathology of U1 small nuclear ribonucleoprotein complex (snRNP), containing U1-70K and its N-terminal cleavage product (N40K), with RNA splicing alteration. To determine whether U1 snRNP dysfunction may play a causative role in AD, we generate a transgenic mouse model (N40K-Tg) by neuronal expression of N40K. Deep transcriptomic analysis of N40K-Tg mice was performed to evaluate intron-retaining mRNAs. Tissue was extracted from hippocampus at three month and twelve month comparing N40K-Tg vs WT mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE115177 | GEO | 2022/08/11

REPOSITORIES: GEO

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Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [N40K neuron RNA-seq]

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A U1-70K Protein Interaction Network Reveals a Functional Class of RNA Binding Proteins with Mixed Charge Domains

Project description:U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) and other proteins of the spliceosome complex are mislocalized to cytoplasmic aggregates in Alzheimer’s disease (AD) brain, yet understanding of the specific mechanisms that cause their aggregation is limited. Many of the RNA binding proteins (RBPs) that aggregate in neurodegenerative diseases, including TDP-43 and FUS, self-assemble into RNA granules through disordered low complexity (LC) domains. We report here that a LC domain within U1-70K, that is comprised of tandem arrays of basic (R/K) and acidic (D/E) residues, shares many of the same properties of the Q/N-rich prion-like LC domains found in TDP-43 and FUS. These properties include the ability to self-assemble into oligomers, and to form nuclear granules in cells. To analyze the functional roles of the U1-70K LC domains, we performed co-immunoprecipitation of recombinant U1-70K and deletions lacking the C-terminal LC domain(s) followed by quantitative proteomics. Using a network-driven approach, functional classes of U1-70K interacting proteins were identified that showed a varying dependency on the U1-70K LC domain(s) for their interaction. We characterize a family of structurally homologous RBPs containing U1-70K LC1-like domains including LUC7L3 and RBM25, which require their respective LC1-like domains for reciprocal interactions with U1-70K and for participation in nuclear RNA granules. Finally, we also show that the LC1 domain of U1-70K can interact with Tau from AD brain supporting a hypothesis that mixed charge structural motifs on U1-70K and other RBPs could mediate cooperative interactions with pathological tau isoforms

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