C9orf72 poly-PR helps p53 escape from the ubiquitin-proteasome system and promotes its stability.

C9orf72-derived dipeptide repeats (DPRs) proteins have been regarded as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). As the most toxic DPRs in C9-ALS/FTD, poly-proline-arginine (poly-PR) is associated with the stability and accumulation of p53, which consequently induces neurodegeneration. However, the exact molecular mechanism via which C9orf72 poly-PR stabilizes p53 remains unclear. In this study, we showed that C9orf72 poly-PR induces not only neuronal damage but also p53 accumulation and p53 downstream gene activation in primary neurons. C9orf72 (PR)50 also slows down p53 protein turnover without affecting the p53 transcription level and thus promotes its stability in N2a cells. Interestingly, the ubiquitin-proteasome system but not the autophagy function was impaired in (PR)50 transfected N2a cells, resulting in defective p53 degradation. Moreover, we found that (PR)50 induces mdm2 mistranslocation from the nucleus to the cytoplasm and competitively binds to p53, reducing mdm2-p53 interactions in the nucleus in two different (PR)50 transfected cells. Our data strongly indicate that (PR)50 reduces mdm2-p53 interactions and causes p53 to escape from the ubiquitin-proteasome system, promoting its stability and accumulation. Inhibiting or at least downregulating (PR)50 binding with p53 may be therapeutically exploited for the treatment of C9-ALS/FTD.

Oxytocin Alleviates MPTP-Induced Neurotoxicity in Mice by Targeting MicroRNA-26a/Death-Associated Protein Kinase 1 Pathway.

Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α-synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro. Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT.

Involvement of calpain in the neuropathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common (60% to 80%) age-related disease associated with dementia and is characterized by a deterioration of behavioral and cognitive capacities leading to death in few years after diagnosis, mainly due to complications from chronic illness. The characteristic hallmarks of the disease are extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) with neuropil threads, which are a direct result of amyloid precursor protein (APP) processing to Aß, and τ hyperphosphorylation. However, many indirect underlying processes play a role in this event. One of these underlying mechanisms leading to these histological hallmarks is the uncontrolled hyperactivation of a family of cysteine proteases called calpains. Under normal physiological condition calpains participate in many processes of cells' life and their activation is tightly controlled. However, with an increase in age, increased oxidative stress and other excitotoxicity assaults, this regulatory system becomes impaired and result in increased activation of these proteases involving them in the pathogenesis of various diseases including neurodegeneration like AD. Reviewed here is a pool of data on the implication of calpains in the pathogenesis of AD, the underlying molecular mechanism, and the potential of targeting these enzymes for AD therapeutics.

Codonopsis pilosula Polysaccharide Attenuates Tau Hyperphosphorylation and Cognitive Impairments in hTau Infected Mice.

Codonopsis pilosula polysaccharide (CPPs), a natural products with potentially lower toxicity and better bioavailability has been used in traditional Chinese medicine for 1000s of years and a neuroprotective polysaccharide mitigates tau pathology in Alzheimer's disease (AD) mouse model. However, whether CPPs can relieve AD pathology and cognitive defects remains poorly understood. Here we reported that CPPs remarkably increased the cell viability and PP2A activity, decreased tau phosphorylation in HEK 293/tau cells. Next, we employed an adeno-associated virus serotype 2 (AAV2)-induced expression of human full length tau (hTau) in C57/BL6 mice to mimic AD tau pathology. One month intragastric administration of CPPs significantly increased PP2A activity and reduced tau phosphorylation at Ser199, Ser202/Thr205 (AT8) and Thr231 in hippocampus of AAV2-hTau infected mice. Furthermore, behavioral tests revealed that CPPs rescued hTau overexpression induced cognitive defects while CPPs significantly increased the fEPSP slope and synaptic proteins including synaptotagmin and synaptophysin. Together, our data suggest that CPPs might prevent AD-like tau hyperphosphorylation via activation of PP2A and attenuates AD-like cognitive impairments through restoring the synaptic plasticity and synaptogenesis. In conclusion, our findings suggest that CPPs might be a potential candidate compound for the treatment of tau related diseases.

Methanolic extract of Tamarix Gallica attenuates hyperhomocysteinemia induced AD-like pathology and cognitive impairments in rats.

Although few drugs are available today for the management of Alzheimer's disease (AD) and many plants and their extracts are extensively employed in animals' studies and AD patients, yet no drug or plant extract is able to reverse AD symptoms adequately. In the present study, Tamarix gallica (TG), a naturally occurring plant known for its strong antioxidative, anti-inflammatory and anti-amyloidogenic properties, was evaluated on homocysteine (Hcy) induced AD-like pathology and cognitive impairments in rats. We found that TG attenuated Hcy-induced oxidative stress and memory deficits. TG also improved neurodegeneration and neuroinflammation by upregulating synaptic proteins such as PSD95 and synapsin 1 and downregulating inflammatory markers including CD68 and GFAP with concomitant decrease in proinflammatory mediators interlukin-1ß (IL1ß) and tumor necrosis factor α (TNFα). TG attenuated tau hyperphosphorylation at multiple AD-related sites through decreasing some kinases and increasing phosphatase activities. Moreover, TG rescued amyloid-ß (Aß) pathology through downregulating BACE1. Our data for the first time provide evidence that TG attenuates Hcy-induced AD-like pathological changes and cognitive impairments, making TG a promising candidate for the treatment of AD-associated pathological changes.