Recent advances in understanding phosphoinositide signaling in the nervous system.

Eamonn James Dickson

doi:10.12688/f1000research.16679.1

Abstract

Polyphosphoinositides (PPIn) are essential signaling phospholipids that make remarkable contributions to the identity of all cellular membranes and signaling cascades in mammalian cells. They exert regulatory control over membrane homeostasis via selective interactions with cellular proteins at the membrane–cytoplasm interface. This review article briefly summarizes our current understanding of the key roles that PPIn play in orchestrating and regulating crucial electrical and chemical signaling events in mammalian neurons and the significant neuro-pathophysiological conditions that arise following alterations in their metabolism.

Highlights

Polyphosphoinositides (PPIn) are a family of minor, negatively charged phospholipid molecules found on the cytoplasmic leaflet of all cellular membranes that play critical roles in membrane homeostasis and cellular signaling[1]
Biogenesis, distribution, and roles of polyphosphoinositides in the nervous system To begin, we focus on the biogenesis of each individual PPIn species and their membrane distribution and define their cellular roles in healthy cells of the nervous system
There are significant questions that remain unanswered in neurons, including the steady-state cellular distribution/metabolism of PtdIns and how this may be affected during signaling reactions or disease, and the role of membrane contact site proteins that transport PtdIns, such as TMEM2413

Summary

Introduction

Polyphosphoinositides (PPIn) are a family of minor (low-abundance), negatively charged phospholipid molecules found on the cytoplasmic leaflet of all cellular membranes that play critical roles in membrane homeostasis and cellular signaling[1]. These data underscore the importance of PtdIns transport and metabolism for regulated nervous system function Despite this knowledge, there are significant questions that remain unanswered in neurons, including the steady-state cellular distribution/metabolism of PtdIns and how this may be affected during signaling reactions or disease, and the role of membrane contact site proteins that transport PtdIns, such as TMEM2413. Further emphasizing the link between dysfunction in early endocytic traffic and Parkinson’s disease, loss-of-function mutations in the ER-lysosome tethering protein VPS13C result in a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline[135,136] These highlighted examples fully underscore the importance of regulated PPIn metabolism for human health. Given the ubiquitous distribution of PPIn across all mammalian cells, the scale of the PPIn interactome, and their essential role in choreographing critical signaling events, it is perhaps inevitable that every human disease will exhibit some form of PPIn dysfunction

Conclusions and future directions

Findings

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