A novel parkin-mediated transcriptional function links p53 to familial Parkinson's disease.

International audienc

The extracellular regulated kinase-1 (ERK1) controls regulated {alpha}-secretase-mediated processing, promoter transactivation and mRNA levels of the cellular prion protein.

International audienceThe α-secretases A Disintegrin And Metalloprotease 10 (ADAM10) and ADAM17 trigger constitutive and regulated processing of the cellular prion protein (PrPc) yielding N1 fragment. The latter depends on protein kinase C (PKC)-coupled M1/M3 muscarinic receptors activation and subsequent phosphorylation of ADAM17 on its intracytoplasmic threonine 735. Here we show that regulated PrPc processing and ADAM17 phosphorylation and activation are controlled by the Extracellular-Regulated Kinase-1/MAP-ERK Kinase (ERK1/MEK) cascade. Thus, reductions of ERK1 or MEK activities by dominant negative analogs, pharmacological inhibition or genetic ablation all impair N1 secretion while constitutively active proteins increase N1 recovery in the conditioned medium. Interestingly, we also observed an ERK1-mediated enhanced expression of PrPc. We demonstrate that ERK1-associated increase in PrPc promoter transactivation and mRNA levels involves the transcription factor AP-1 as a downstream effector. Altogether, our data identify ERK1 as an important regulator of PrPc cellular homeostasis and indicate that this kinase exerts a dual control of PrPc levels through transcriptional and post-transcriptional mechanisms

Melatonin stimulates the nonamyloidogenic processing of βAPP through the positive transcriptional regulation of ADAM10 and ADAM17

Melatonin controls many physiological functions including regulation of the circadian rhythm and clearance of free radicals and neuroprotection. Importantly, melatonin levels strongly decrease as we age and patients with Alzheimer's disease (AD) display lower melatonin than age-matched controls. Several studies have reported that melatonin can reduce aggregation and toxicity of amyloid-beta peptides that are produced from the beta-amyloid precursor protein (beta APP). However, whether melatonin can directly regulate the beta APP-cleaving proteases ('secretases') has not been investigated so far. In this study, we establish that melatonin stimulates the alpha-secretase cleavage of beta APP in cultured neuronal and non-neuronal cells. This effect is fully reversed by ADAM10- and ADAM17-specific inhibitors and requires both plasma membrane-located melatonin receptor activation, and ERK1/2 phosphorylation. Moreover, we demonstrate that melatonin upregulates both ADAM10 and ADAM17 catalytic activities and endogenous protein levels. Importantly, genetic depletion of one or the other protease in mouse embryonic fibroblasts prevents melatonin stimulating constitutive and PKC-regulated sAPP alpha secretion and ADAM10/ADAM17 catalytic activities. Furthermore, we show that melatonin induces ADAM10 and ADAM17 promoter transactivation, and we identify the targeted promoter regions. Finally, we correlate melatonin-dependent sAPP alpha production with a protection against staurosporine-induced apoptosis. Altogether, our results provide the first demonstration that melatonin upregulates the nonamyloidogenic ADAM10 and ADAM17 proteases through melatonin receptor activation, ERK phosphorylation and the transactivation of some specific regions of their promoters and further underline the preventive rather than curative nature of melatonin regarding AD treatment

Intraneuronal Aβ42 Accumulation in Human Brain

Alzheimer’s disease (AD) is characterized by the deposition of senile plaques (SPs) and neurofibrillary tangles (NFTs) in vulnerable brain regions. SPs are composed of aggregated β-amyloid (Aβ) 40/42(43) peptides. Evidence implicates a central role for Aβ in the pathophysiology of AD. Mutations in βAPP and presenilin 1 (PS1) lead to elevated secretion of Aβ, especially the more amyloidogenic Aβ42. Immunohistochemical studies have also emphasized the importance of Aβ42 in initiating plaque pathology. Cell biological studies have demonstrated that Aβ is generated intracellularly. Recently, endogenous Aβ42 staining was demonstrated within cultured neurons by confocal immunofluorescence microscopy and within neurons of PS1 mutant transgenic mice. A central question about the role of Aβ in disease concerns whether extracellular Aβ deposition or intracellular Aβ accumulation initiates the disease process. Here we report that human neurons in AD-vulnerable brain regions specifically accumulate γ-cleaved Aβ42 and suggest that this intraneuronal Aβ42 immunoreactivity appears to precede both NFT and Aβ plaque deposition. This study suggests that intracellular Aβ42 accumulation is an early event in neuronal dysfunction and that preventing intraneuronal Aβ42 aggregation may be an important therapeutic direction for the treatment of AD