The amyloid precursor protein (APP) binds the PIKfyve complex and modulates its function

Abstract

Phosphoinositides are important components of eukaryotic membranes that are required for multiple forms of membrane dynamics. Phosphoinositides are involved in defining membrane identity, mediate cell signalling and control membrane trafficking events. Due to their pivotal role in membrane dynamics, phosphoinositide de-regulation contributes to various human diseases. In this review, we will focus on the newly emerging regulation of the PIKfyve complex, a phosphoinositide kinase that converts the endosomal phosphatidylinositol-3-phosphate [PI(3)P] to phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2)], a low abundance phosphoinositide of outstanding importance for neuronal integrity and function. Loss of PIKfyve function is well known to result in neurodegeneration in both mouse models and human patients. Our recent work has surprisingly identified the amyloid precursor protein (APP), the central molecule in Alzheimer's disease aetiology, as a novel interaction partner of a subunit of the PIKfyve complex, Vac14. Furthermore, it has been shown that APP modulates PIKfyve function and PI(3,5)P2 dynamics, suggesting that the APP gene family functions as regulator of PI(3,5)P2 metabolism. The recent advances discussed in this review suggest a novel, unexpected, β-amyloid-independent mechanism for neurodegeneration in Alzheimer's disease.

Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol

“…Additionally, recessive mutations of vac14 in humans also lead to progressive neurodegeneration (74). Recently, it was also found that the VAC14 protein complex binds to amyloid precursor protein (APP), a protein essential to the development of Alzheimer's disease (75)(76)(77). There have been several studies of the link between cholesterol and Alzheimer's disease (78)(79)(80) and even trials of cholesterol-reducing drugs as potential therapeutics for patients with the disease (81,82).…”

Defective phosphoinositide metabolism in autism

“…Mutations in FIG4 were also found in Yunis‐Varon syndrome, a neurological disorder with skeletal defects and severe neuronal loss in the central nervous system (Nakajima et al, ), as well as in some forms of amyloid lateral sclerosis, although a causal link has not yet been proved (Chow et al, ). Last but not least and as discussed above, FIG4 is part of the PIKfyve complex, which has been shown to be regulated by APP and, thus, may play a role in Alzheimer's disease (Currinn et al, ; Currinn and Wassmer, ). Mutations in a different phosphoinositide phosphatase, MTM‐related 2 ( MTMR2 ), which dephosphorylates both PI(3,5)P 2 and PI(3)P at the third hydroxyl group, lead to another form of Charcot‐Marie‐Tooth disease, CMT4B1 (Bolino et al, ).…”

A Click‐Chemistry‐Based Enrichable Crosslinker for Structural and Protein Interaction Analysis by Mass Spectrometry

“…Proteins need to interact with other proteins to form functional complexes. In many cases, protein function inside cells cannot be understood without information about the protein structure and knowledge of in which complex the protein is situated . This is, for example, of paramount importance for proteins that modulate epigenetic information on DNA.…”