PACSIN proteins in vivo: Roles in development and physiology

Abstract

Protein kinase C and casein kinase substrate in neurons (PACSINs), or syndapins (synaptic dynamin‐associated proteins), are a family of proteins involved in the regulation of cell cytoskeleton, intracellular trafficking and signalling. Over the last twenty years, PACSINs have been mostly studied in the in vitro and ex vivo settings, and only in the last decade reports on their function in vivo have emerged. We first summarize the identification, structure and cellular functions of PACSINs, and then focus on the relevance of PACSINs in vivo. During development in various model organisms, PACSINs participate in diverse processes, such as neural crest cell development, gastrulation, laterality development and neuromuscular junction formation. In mouse, PACSIN2 regulates angiogenesis during retinal development and in human, PACSIN2 associates with monosomy and embryonic implantation. In adulthood, PACSIN1 has been extensively studied in the brain and shown to regulate neuromorphogenesis, receptor trafficking and synaptic plasticity. Several genetic studies suggest a role for PACSIN1 in the development of schizophrenia, which is also supported by the phenotype of mice depleted of PACSIN1. PACSIN2 plays an essential role in the maintenance of intestinal homeostasis and participates in kidney repair processes after injury. PACSIN3 is abundant in muscle tissue and necessary for caveolar biogenesis to create membrane reservoirs, thus controlling muscle function, and has been linked to certain genetic muscular disorders. The above examples illustrate the importance of PACSINs in diverse physiological or tissue repair processes in various organs, and associations to diseases when their functions are disturbed.

Omnibus proteome-wide association study (PWAS-O) identified 43 risk genes for Alzheimer’s disease dementia

“…The novel gene PLA2G7 was shown to have biological function involved in inflammatory and oxidative activities 39 , and with a known association with AD and cognitive decline 40 . The novel gene PACSIN3 has been implicated in the disorders of the central nervous system such as schizophrenia 41 .…”

Decreased methylglyoxal-mediated protein glycation in the healthy aging mouse model of ectopic expression of UCP1 in skeletal muscle

“…Activity of creatinine kinase-B declines in aging and is inhibited by MG modification [ 65 , 66 ]. PACSIN3 is involved in caveolae and muscle repair [ 67 ], and β-actin and γ-actin are modified by MG in the Mg 2+− ADP binding site and ubiquitination site, respectively, which likely impairs functional activity and degradation, respectively [ 68 ]. Decrease of this and proteomic restructuring of skeletal muscle may provide for improved metabolic and muscular health in aging.…”

PACSIN2as a modulator of autophagy and mercaptopurine cytotoxicity: mechanisms in lymphoid and intestinal cells

“…PACSINs are proteins that functionally link actin cytoskeleton and vesicle formation by regulating tubulin polymerization, and exert their function mainly through protein–protein interactions with different substrates, such as N-WASP or dynamin. PACSINs have various biological roles, including modulation of endocytosis ( de Kreuk et al, 2011 ; Dumont & Lehtonen, 2022 ) and membrane tubulation in cells such as megakaryocytes, likely contributing to platelet formation ( Shimada et al, 2010 ; Dumont & Lehtonen, 2022 ). PACSIN2 presents a high sequence homology with PACSIN1, which is implicated in signaling networks that control autophagy under optimal growth conditions ( Szyniarowski et al, 2011 ; Oe et al, 2022 ).…”

“…We performed immunoblotting using 10 μg of cell lysate. (de Kreuk et al, 2011;Dumont & Lehtonen, 2022) and membrane tubulation in cells such as megakaryocytes, likely contributing to platelet formation (Shimada et al, 2010;Dumont & Lehtonen, 2022).…”