Conserved Signals in Neurodegeneration

Science Signaling  25 Jun 2013:
Vol. 6, Issue 281, pp. ec143
DOI: 10.1126/scisignal.2004445

The accumulation of abnormal proteins mediates the pathogenesis of various neurodegenerative diseases. The accumulation and phosphorylation of a form of ataxin 1 (ATXN1) that has an expanded polyglutamine tract [ATXN1(82Q)] causes spinocerebellar ataxia type 1 (SCA1). Park et al. found that members and regulators of the mitogen-activated protein kinase (MAPK) pathway increased the abundance of ATXN1(82Q). In Drosophila, silencing homologs of ERK (extracellular signal–regulated kinase), MEK (a MAPK kinase that activates ERK and MSK1), or MSK1 (mitogen- and stress-activated protein kinase 1) decreased motor performance deficits and improved lifespan in a fly model of SCA1. Knockdown of MSK1, which in vitro phosphorylated both wild-type ATXN1 and ATXN1(82Q) at Ser776 within an evolutionarily conserved motif, also decreased the stability of ATXN1(82Q) in fly head lysates. Conversely, the overexpression of MSK1 in mouse Neuro2a cells increased the stability of ATXN1(82Q) in a Ser776-dependent manner, and MSK1 abundance correlated with the phosphorylation of ATXN1 in cerebellar fractions from wild-type mice. Either knockdown or pharmacological inhibition of MSK1 or MAPK pathway components upstream of MSK1, including RAS and MEK, in human medulloblastoma cells or mouse Neuro2a cells expressing ATXN1(82Q) or cerebellar slice cultures from ATXN1(82Q) knock-in mice also decreased the phosphorylation and abundance of ATXN1(82Q). Motor performance of Atxn1154Q/+ mice, a model of human SCA1, was improved in mice heterozygous for both Msk1 and Msk2, but not single Msk1 or Msk2 heterozygotes. Deletion of one copy of Msk1 or the simultaneous deletion of one copy of Msk1 and Msk2 in B05/+ mice (a neurodegeneration mouse model) partially reduced both the abundance of ATXN1(82Q) and Purkinje cell loss, features of SCA1. Furthermore, compared with control B05/+ mice, Purkinje cell dendrites in Msk1–/+/Msk2–/+ B05/+ mice had increased abundance of calbindin, a calcium-binding protein important for motor coordination. Together, the findings suggest that targeting the MAPK pathway may improve neurodegeneration and motor deficits in SCA1.

J. Park, I. Al-Ramahi, Q. Tan, N. Mollema, J. R. Diaz-Garcia, T. Gallego-Flores, H.-C. Lu, S. Lagalwar, L. Duvick, H. Kang, Y. Lee, P. Jafar-Nejad, L. S. Sayegh, R. Richman, X. Liu, Y. Gao, C. A. Shaw, J. S. C. Arthur, H. T. Orr, T. F. Westbrook, J. Botas, H. Y. Zoghbi, RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 498, 325–331 (2013). [PubMed]