Progress on loss-of-function hypothesis of presenilin-1 mutations in Alzheimer diseases / 浙江大学学报·医学版

Alzheimer's disease (AD) is an aging-related neurodegenerative disease and is associated with the accumulation of amyloid-β (Aβ) peptides in patient brains. AD can be classified into the familial type and sporadic type. () is the major risk gene for familial AD (fAD) because its mutations comprised over 80%of the total mutations causing fAD. PS1 is the catalytic subunit of the enzyme γ-secretase, which is responsible for the proteolytic cleavage of amyloid precursor protein (APP) to produce Aβ. Although novel fAD-causing mutations in PS1 are being reported increasingly, the molecular mechanisms underlying how these mutations induce fAD remain elusive. Since over 90%of the fAD-causing mutations in PS1 leads to a reduction of γ-secretase activity, the loss-of-function mutation hypothesis has been emerged, which suggests that the loss of PS1 functions may be the root cause of AD. Recently, increasing number of evidence supports this hypothesis. First, loss-of-function mutations increase the production of long-length Aβ by disturbing the cleavage sites of γ-secretase APP, thereby increasing the ratio of Aβ/Aβ; Second, loss-of-function mutations dysregulate endoplasmic reticulum calcium homeostasis in neurons; Third, loss-of-function mutations inhibit the autophagy activity of neurons, resulting in the abnormal accumulation of cleaved products from APP; Fourth, loss-of-function mutations alter the endocytosis and transcytosis processes in neurons, leading to neuratrophy; Fifth, loss-of-function mutations activate brain immune cells (astrocytes and microglia), which mount a strong neuroinflammation response; Last, loss-of-function mutations reduce the rates of glycolysis and the production of lactic acid, disrupting the balance of neuronal energy supply. In this article we summary the research progress on the loss-of-function hypothesis and pose several topics which would guide studies of this field in future.

Filaggrin mutations and the skin.

Filaggrin is very important in the terminal differentiation of the skin and the formation of cornified envelope in the stratum corneum. Several mutations in the filaggrin gene have been identified in the last decade, mostly from the European countries. Loss of function mutations in the filaggrin gene results in reduced production of filaggrin, depending on the type and site of mutation. Such mutations in the filaggrin gene have been shown to be the most significant genetic risk factor for development of atopic dermatitis and undoubtedly has a role in the pathogenesis of ichthyosis vulgaris. Though there is theoretical possibility of association with hand eczema and allergic contact dermatitis; in clinical studies, the strength of these associations was not significantly strong. In this review, we have discussed the structure and function of filaggrin, basic genetics, type of mutations in filaggrin gene, and association of such mutations with different dermatoses.