Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation, and triggers neurodegeneration. AEP is upregulated and active during aging, and is activated in tau P301S transgenic mice and human AD brain, leading to tau truncation in NFTs. Deletion of AEP from tau P301S transgenic mice substantially reduces tau hyperphosphorylation, alleviates the synapse loss and rescues impaired hippocampal synaptic function and the cognitive deficits. Infection of uncleavable tau N255AN368A mutant rescues tau P301S-induced pathological and behavioral defects. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes in neurodegenerative diseases. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.

RPS3, a conserved, eukaryotic ribosomal protein of the 40 S subunit, is required for ribosome biogenesis. Because ribosomal proteins are abundant and ubiquitous, they may have additional extraribosomal functions. Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3. RPS3 induced neuronal apoptosis, up-regulating proapoptotic proteins Dp5/Hrk and Bim by binding to E2F1 and acting synergistically with it. Akt-dependent phosphorylation of RPS3 inhibited its proapoptotic function and perturbed its interaction with E2F1. These events coincided with nuclear translocation and accumulation of RPS3, where it functions as an endonuclease. Nuclear accumulation of RPS3 results in an increase in DNA repair activity to some extent, thereby sustaining neuronal survival. Abolishment of Akt-mediated RPS3 phosphorylation through mutagenesis accelerated apoptotic cell death and severely compromised nuclear translocation of RPS3. Thus, our findings define an extraribosomal role of RPS3 as a molecular switch that accommodates apoptotic induction to DNA repair through Akt-mediated phosphorylation.Nerve growth factor (NGF) deprivation and DNA damage can activate the intrinsic apoptotic pathway, causing cytochrome c release and caspase-dependent cell death in many cell types, including sympathetic neurons (1-5). NGF regulates neuronal apoptosis through a variety of cellular signaling mechanisms, especially the phosphoinositide 3-kinase (PI3K)/Akt pathway (6). Akt signaling promotes cell survival by phosphorylating and controlling downstream effectors in both the cytoplasm and the nucleus. For instance, Akt phosphorylates the proapoptotic Bcl-2 family member BAD (7) that belongs to the cytoplasmic apoptotic apparatus. In addition, Akt inhibits chromatin condensation during apoptosis by phosphorylating ACINUS, a nuclear factor required for apoptotic chromatin condensation (8). PI3K and Akt are predominantly located in the cytoplasm, but they are also found in the nucleus or translocate there upon stimulation by growth factors (9 -11) or DNA damage (9 -12).Ribosomal protein S3 (RPS3) is a component of the 40 S ribosomal subunit and is involved in its maturation (13). A growing body of evidence suggests that ribosomal proteins are capable of extraribosomal functions. For example, RPS3, also known as UV endonuclease III, appears to possess a general base damage endonuclease that participates in the cleavage of DNA lesions caused by UV irradiation. In addition, both RPS3 and ribosomal protein P0 have an apurinic/apyrimidinic (AP) 2 endonuclease activity functioning in DNA repair at the 3Ј side of AP sites after DNA damage (14 -16). In addition, ribosomal proteins may have apoptotic functions as follows: RPS3-a is involved in the apoptotic process in NIH3T3 cells (17), and knockdown of rpS3 leads to significant cell survival after hydrogen peroxid...

Serine-arginine protein kinases 2 (SRPK2) is a cell cycle-regulated kinase that phosphorylates serine/arginine domain-containing proteins and mediates pre-mRNA splicing with unclear function in neurons. Here, we show that SRPK2 phosphorylates tau on S214, suppresses tau-dependent microtubule polymerization and inhibits axonal elongation in neurons. Depletion of SRPK2 in dentate gyrus inhibits tau phosphorylation in APP/PS1 mouse and alleviates the impaired cognitive behaviors. The defective LTP in APP/PS1 mice is also improved after SRPK2 depletion. Moreover, active SRPK2 is increased in the cortex of APP/PS1 mice and the pathological structures of human Alzheimer’s disease (AD) brain. Therefore, our study suggests SRPK2 may contribute to the formation of hyperphosphorylated tau and the pathogenesis of AD.