Defective autophagy and Alzheimer’s disease: is calcium the key?

Riccardo Filadi; Paola Pizzo

doi:10.4103/1673-5374.262584

摘要：Presenilins and autophagy: Presenilin 1 (PS1) and presenilin 2 (PS2) are homologous, multi-pass transmembrane proteins endowed with pleiotropic functions, ranging from the regulation of membrane traf-ficking to cell differentiation. Their catalytic activity within the γ-secre-tase complex, an aspartyl-protease responsible for the intramembrane cleavage of several different type I transmembrane proteins, has been intensively studied in the context of Alzheimer’s disease (AD). Indeed, tens of autosomal dominant mutations in the PSEN1 and PSEN2 genes (encoding PS1 and PS2, respectively) have been associated with the rare familial forms of AD (FAD). FAD-PS1/PS2 mutants are known to alter the γ-secretase-dependent cleavage of the amyloid-precursor-pro-tein, generating amyloid-β (Aβ) peptides, whose toxicity is thought to underlie AD onset and progression. Interestingly, in the last decade, besides their γ-secretase activity, both PS1 and PS2 have been implicat-ed in the regulation of macroautophagy (hereafter called autophagy), a key cellular pathway in which different cell material (proteins, lipids, sugars, damaged organelles) is engulfed within double-membrane ves-icles (autophagosomes) and targeted to lysosomes for degradation and recycling of the molecular constituents. Considered that impairment of autophagy can promote neurodegeneration, the finding that FAD-linked PSs perturb this process suggests it could be involved in AD pathogenesis.