Biochemistry and cell biology approaches are used to explore the pathogenic mechanism of familial AD mutations. We are currently characterizing two early onset AD mutations on APP and PSEN1 genes identified from Taiwanese families to understand their contribution in AD.
Around 0.1% of the AD cases are early-onset (before age 65) familial forms of the autosomal dominant inheritance, attributed to mutations in one of the three genes: those encoding amyloid precursor protein (APP), and presenilin-1 (PS1) and -2 (PS2). Genetic predisposition provides a powerful tool to reveal the pathogenic mechanisms of the disease.
Our group characterizes pathogenic mechanisms of two mutations, encoding APPD678H and PS1G206D mutants, found in Taiwanese pedigrees. One of the pathogenic hallmarks of the disease is the amyloid plaque, in which abnormal concentrated amyloid beta (Aβ) peptide and metal ions deposit. Aβ peptide is currently considered to be the major trigger of the disease and is produced by sequential cleavage of β- and γ-secretase on APP. PS1 is the catalytic component of the γ-secretase complex and Pen2 is a critical co-factor for γ-secretase activity.
The APPD678H mutation
APPD678H has an additional metal ion-coordinating residue, histidine (H). We speculate that this mutation may promote susceptibility of Aβ to ions. We found that the D678H mutation increases Aβ production and prolonged Aβ oligomer state with higher neurotoxicity. D678H also increases Aβ susceptibility to zinc and copper, which lead to altered aggregation pathway. Therefore, our study not only characterizes the D678H mutant Aβ aggregation pathway in detail, but also first time provides a genetic evidence for the importance of zinc and copper in the disease.
The PS1G206D mutation
PS1G206D provides an additional polar transmembrane-based amino acid, aspartate (D), near the Pen2 binding site. We speculate that this mutation may interfere with the Pen2 binding and PS1 functions. We found that the G206D mutation decreases PS1-Pen2 interaction, but does not abolish γ-secretase activity. For γ-secretase dependent function, the G206D mutation alters the proportion of Aβ varieties, but does not alter Notch cleavage. For γ-secretase independent function, this mutation disrupts the calcium homeostasis but not endo-lysosomal functions. Therefore, our study not only characterizes the general functions of PS1 G206D mutant in detail, but also first time provides genetic evidence for the importance of PS1-Pen2 interaction in the disease.
Together, genetic tool helps us to dissect the pathogenic mechanism in cellular models and that could further provide therapeutic target for the disease. We highlight the importance of Aβ-ions, calcium imbalance and PS1-Pen2 interaction in AD pathology.
The Non coding DNA
According to previous research, human only use 8.2% of the whole DNA to code functional proteins. It can also be said that 90% of human genome is a “junk” or scientifically non coding DNA (ncDNA). However, people wonder that it must not be only a junk, but they must be doing something. Long non-coding RNA (lncRNAs) can be categorized as a subgroup of non-coding RNA, which the size is longer than 200 nucleotides. Some previous researches have demonstrated that lncRNAs involved in variety of tasks, for example, post-transcriptional regulation, splicing regulation, protein complex organization, cell-cell signaling, and so on. Our lab is trying to reveal the participation of lncRNA in Alzheimer’s Disease.