Bilateral crosstalk of rho- and extracellular-signal-regulated-kinase (ERK) pathways is confined to an unidirectional mode in spinal muscular atrophy (SMA)

Niko Hensel; Inga Stockbrügger; Sebastian Rademacher; Natasha Broughton; Hella Brinkmann; Claudia Grothe; Peter Claus

doi:10.1016/j.cellsig.2013.11.027

Bilateral crosstalk of rho- and extracellular-signal-regulated-kinase (ERK) pathways is confined to an unidirectional mode in spinal muscular atrophy (SMA)

Cell Signal. 2014 Mar;26(3):540-8. doi: 10.1016/j.cellsig.2013.11.027. Epub 2013 Dec 3.

Authors

Niko Hensel¹, Inga Stockbrügger², Sebastian Rademacher¹, Natasha Broughton², Hella Brinkmann², Claudia Grothe¹, Peter Claus³

Affiliations

¹ Institute of Neuroanatomy, Hannover Medical School, 30625 Hannover, Germany; Center for Systems Neuroscience (ZSN), 30559 Hannover, Germany.
² Institute of Neuroanatomy, Hannover Medical School, 30625 Hannover, Germany.
³ Institute of Neuroanatomy, Hannover Medical School, 30625 Hannover, Germany; Center for Systems Neuroscience (ZSN), 30559 Hannover, Germany; Niedersachsen Research Network on Neuroinfection (N-RENNT), Germany. Electronic address: [email protected].

PMID: 24316236
DOI: 10.1016/j.cellsig.2013.11.027

Abstract

Rho-kinase (ROCK) as well as extracellular signal regulated kinase (ERK) control actin cytoskeletal organization thereby regulating dynamic changes of cellular morphology. In neurons, motility processes such as axonal guidance and neurite outgrowth demand a fine regulation of upstream pathways. Here we demonstrate a bilateral ROCK-ERK information flow in neurons. This process is shifted towards an unidirectional crosstalk in a model of the neurodegenerative disease Spinal Muscular Atrophy (SMA), ultimately leading to neurite outgrowth dysregulations. As both pathways are of therapeutic relevance for SMA, our results argue for a combinatorial ROCK/ERK-targeting as a future treatment strategy.

Keywords: (ERK); (ROCK); (SMA); Neurite outgrowth; Nuclear protein; Rho-kinase; Spinal Muscular Atrophy; Survival of motoneuron protein; extracellular signal regulated kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actin Cytoskeleton / metabolism
Amides / pharmacology
Animals
Cell Line
Cell Proliferation
Enzyme Inhibitors / pharmacology
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism*
Mice
Muscular Atrophy, Spinal / pathology*
Neurites / pathology*
PC12 Cells
Pyrazoles / pharmacology
Pyridazines / pharmacology
Pyridines / pharmacology
Pyrimidines / pharmacology
RNA Interference
RNA, Small Interfering
Rats
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptors, Fibroblast Growth Factor / antagonists & inhibitors
SMN Complex Proteins / genetics*
rho-Associated Kinases / antagonists & inhibitors
rho-Associated Kinases / genetics
rho-Associated Kinases / metabolism*

Substances

Amides
Enzyme Inhibitors
FR 180204
PD 173074
Pyrazoles
Pyridazines
Pyridines
Pyrimidines
RNA, Small Interfering
Receptors, Fibroblast Growth Factor
SMN Complex Proteins
Y 27632
Receptor Protein-Tyrosine Kinases
rho-Associated Kinases
Extracellular Signal-Regulated MAP Kinases