No abstract

Amyloid beta-peptide (Abeta), which plays a central role in Alzheimer's disease, is generated by presenilin-dependent gamma-secretase cleavage of beta-amyloid precursor protein (betaAPP). We report that the presenilins (PS1 and PS2) also regulate Abeta degradation. Presenilin-deficient cells fail to degrade Abeta and have drastic reductions in the transcription, expression, and activity of neprilysin, a key Abeta-degrading enzyme. Neprilysin activity and expression are also lowered by gamma-secretase inhibitors and by PS1/PS2 deficiency in mouse brain. Neprilysin activity is restored by transient expression of PS1 or PS2 and by expression of the amyloid intracellular domain (AICD), which is cogenerated with Abeta, during gamma-secretase cleavage of betaAPP. Neprilysin gene promoters are transactivated by AICDs from APP-like proteins (APP, APLP1, and APLP2), but not by Abeta or by the gamma-secretase cleavage products of Notch, N- or E- cadherins. The presenilin-dependent regulation of neprilysin, mediated by AICDs, provides a physiological means to modulate Abeta levels with varying levels of gamma-secretase activity.

Recent works suggest that ␣-synuclein could play a central role in Parkinson's disease (PD). Thus, two mutations were reported to be associated with rare autosomal dominant forms of the disease. We examined whether ␣-synuclein could modulate the caspase-mediated response and vulnerability of murine neurons in response to various apoptotic stimuli. We established TSM1 neuronal cell lines overexpressing wild-type (wt) ␣-synuclein or the PD-related Ala-53 3 Thr mutant ␣-synuclein. Under basal conditions, acetyl-Asp-Glu-Val-Asp-aldehyde-sensitive caspase activity appears significantly lower in wt ␣-synuclein-expressing cells than in neurons expressing the mutant. Interestingly, wt ␣-synuclein drastically reduces the caspase activation of TSM1 neurons upon three distinct apoptotic stimuli including staurosporine, etoposide, and ceramide C 2 when compared with mock-transfected cells. This inhibitory control of the caspase response triggered by apoptotic agents was abolished by the PD-related pathogenic mutation. Comparison of wildtype and mutated ␣-synuclein-expressing cells also indicates that the former exhibits much less vulnerability in response to staurosporine and etoposide as measured by the sodium 3-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonic acid assay. Altogether, our study indicates that wild-type ␣-synuclein exerts an antiapoptotic effect in neurons that appears to be abolished by the Parkinson's disease-related mutation, thereby suggesting a possible mechanism underlying both sporadic and familial forms of this neurodegenerative disease.Parkinson's disease neuropathology is mainly characterized by proteinaceous deposits called Lewy bodies (1). The main component of these brain lesions is ␣-synuclein (2, 3), a 140-amino acid peptide first identified as the precursor of the "nonamyloidogenic component" (4) of the senile plaques invading the cortical and subcortical areas of both sporadic and familial Alzheimer's disease-affected brains. Of the most interest was the recent demonstration that rare cases of Parkinson's disease were of genetic origin and that two mutations identified on ␣-synuclein were likely responsible for these autosomal forms of the disease (5, 6). It has been suggested that part of the disease etiology is derived from the accelerated aggregation process triggered by the two mutations (7). El Agnaf et al. (8) showed that ␤-sheets-related aggregates of wild-type and mutant ␣-synucleins could trigger apoptotic cell death in human neuroblastoma cells. More recently, Kholodilov et al. (9) demonstrated that ␣-synuclein expression was decreased in the rat substantia nigra after induction of apoptosis by intrastriatal injection of 6-hydroxydopamine. Although these two studies established a possible link between ␣-synucleins and apoptosis, nothing is really known concerning the genuine function of ␣-synuclein.We have taken advantage of the design of a clonal cell line from neocortical origin (TSM1 cells (10)) to examine the possible influence of ␣-synuclein i...