Phosphoinositides: Regulators of Nervous System Function in Health and Disease

Abstract

Phosphoinositides, the seven phosphorylated derivatives of phosphatidylinositol have emerged as regulators of key sub-cellular processes such as membrane transport, cytoskeletal function and plasma membrane signaling in eukaryotic cells. All of these processes are also present in the cells that constitute the nervous system of animals and in this setting too, these are likely to tune key aspects of cell biology in relation to the unique structure and function of neurons. Phosphoinositides metabolism and function are mediated by enzymes and proteins that are conserved in evolution, and analysis of knockouts of these in animal models implicate this signaling system in neural function. Most recently, with the advent of human genome analysis, mutations in genes encoding components of the phosphoinositide signaling pathway have been implicated in human diseases although the cell biological basis of disease phenotypes in many cases remains unclear. In this review we evaluate existing evidence for the involvement of phosphoinositide signaling in human nervous system diseases and discuss ways of enhancing our understanding of the role of this pathway in the human nervous system’s function in health and disease.

Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data

“…The pathways of phosphatidylinositol bisphosphate kinase activity, cyclic adenosine monophosphate (cAMP) response element binding protein, tyrosine kinase and voltage-gated ion channels have a vital functional role in the regulation of the postsynaptic membrane potential. Phosphatidylinositol bisphosphate kinase activity is a lipid second messenger with a number of biological functions such as signal transduction, vesicle trafficking, adhesion, and [ 28 ]. There are limited studies, on the effect of phosphatidylinositol bisphosphate kinase activity on HD.…”

“…A previous study, investigated the in vitro knock down or pharmacological inhibition of the PIP4K isoform, PIP4K2C the study observed a reduction in mHTT aggregates by increasing autophagy. Therefore, proposing that the kinase could be a potential therapeutic target for HD treatment [ 28 ]. The cAMP response element binding protein was also identified, the cAMP-response element binding protein (CREB) is an intracellular protein responsible for the regulation of genes that are vital in DA neurons.…”

“…The phosphoinositide enzyme PI5P has been recently discovered and is located in the plasma membrane, nucleus and Golgi. The possible function of PI5P in the cell, is that it may be involved in regulating chromatin function and transcriptional regulation in the nucleus [ 28 ].…”

“…The study identified a decrease in mHTT protein aggregates was observed by increasing basal autophagy. This study suggested that the PIP4K2C kinase may be a potential target for the treatment progressive neurodegenerative diseases such as HD [ 28 ]. However, more research is needed to investigate and understand the phosphoinositide enzymes and their role in HD.…”

Membrane Binding of Neuronal Calcium Sensor-1: Highly Specific Interaction with Phosphatidylinositol-3-Phosphate

“…This flexibility, in addition to extremely high Ca 2+ -sensitivity and constitutive membrane localization, calls for additional mechanisms of regulation to avoid indiscriminate binding of target proteins by NCS-1. High affinity to phosphoinositides could help compartmentalize NCS-1 with its targets in the appropriate conditions, as phosphoinositides are distributed in distinct spatial patterns, which fluctuate in response to stimuli (reviewed in [58]). For example, the ability to discern PI3P and PI4P could be of great importance for NCS-1, as by binding PI4P it could sequester the substrate of its own regulatory target phosphatidylinositol-4-kinase βIII, that NCS-1 is supposed to activate [59].…”