STOP Proteins are Responsible for the High Degree of Microtubule Stabilization Observed in Neuronal Cells

Abstract

Neuronal differentiation and function require extensive stabilization of the microtubule cytoskeleton. Neurons contain a large proportion of microtubules that resist the cold and depolymerizing drugs and exhibit slow subunit turnover. The origin of this stabilization is unclear. Here we have examined the role of STOP, a calmodulin-regulated protein previously isolated from cold-stable brain microtubules. We find that neuronal cells express increasing levels of STOP and of STOP variants during differentiation. These STOP proteins are associated with a large proportion of microtubules in neuronal cells, and are concentrated on cold-stable, drug-resistant, and long-lived polymers. STOP inhibition abolishes microtubule cold and drug stability in established neurites and impairs neurite formation. Thus, STOP proteins are responsible for microtubule stabilization in neurons, and are apparently required for normal neurite formation.

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

“…The effects of STOP on microtubule dynamic instability are not known. However, STOP is an important factor in determining resistance of microtubules to cold-induced depolymerisation (Guillaud et al, 1998), and thus it may affect microtubule dynamics and could potentially contribute to higher polymerised tubulin content and/or to the reduced rate and extent of MT depolymerisation in mut p53 cells.…”

Un rôle pour le cytosquelette dans les maladies mentales ?

“…Ces dernières années, toutefois, il est devenu évident que la stabilisation des neurotubules résulte largement de l'association de ces polymères avec des protéines contrôlées par la calmoduline, appelées protéines STOP (stable tubule only polypeptide). Dans des cellules neuronales en culture, l'inhibition de l'activité des protéines STOP abolit la stabilité au froid des microtubules et provoque une inhibition de la croissance des neurites [6].…”

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

“…MAP6 is only found in vertebrates and is expressed in several tissues like the brain, heart, muscle, kidney, lung, and testis (Aguezzoul et al 2003). In the brain, MAP6 is expressed in neurons, astrocytes, and oligodendrocytes (Denarier et al 1998b;Galiano et al 2004;Guillaud et al 1998;Ochoa et al 2011). Two main splice isoforms are described in neurons; MAP6-E and MAP6-N (Aguezzoul et al 2003;Denarier et al 1998a).…”

“…MAP6-E is the most abundant isoform in embryonic rodent brain and persists in adult brain. MAP6-N appears at birth and its expression is maintained in the adult brain (Bosc et al 1996;Guillaud et al 1998). MAP6 has a strong preference for stable MTs (Bonnet et al 2002;Slaughter and Black 2003).…”

“…MAP6, also named STOP (stable tubule-only peptides), was discovered as the major factor able to confer cold and nocodazole resistance to neuronal MTs (Andrieux et al 2002;Bosc et al 1996;Guillaud et al 1998). MAP6 is a calmodulin-regulated protein (Job et al 1981(Job et al , 1983.…”