Aberrant Stress-induced Phosphorylation of Perikaryal Neurofilaments

doi:10.1074/jbc.271.48.30404

Aberrant Stress-induced Phosphorylation of Perikaryal Neurofilaments*

From the Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada

^§ To whom reprint requests should be addressed:
Dept. of Biochemistry, McGill University, 3655 Drummond, Montreal, Quebec H3G 1Y6, Canada.
Tel.: 514-398-7286; Fax: 514-398-7384.

Abstract

The aberrant phosphorylation of the neurofilament high molecular weight subunit (NFH) in the neuronal perikaryon is a common feature of several neurological diseases. We demonstrated a strong correlation between hyperphosphorylation of the NFH carboxyl-terminal domain and activation of stress-activated protein kinase (SAPK) -γ in PC12 cells. Agents that activated SAPKγ in PC12 cells also caused the hyperphosphorylation of perikaryal NFH in cultured dorsal root ganglion neurons. The NFH carboxyl-terminal domain was phosphorylated by SAPKγ in vitro, and the use of peptide substrates indicated that this event occurred preferentially at KSPXE motifs. We propose that SAPKγ, perhaps in concert with other SAPKs, is involved in the abnormal phosphorylation of perikaryal NFH. This finding could lead to new insights into the etiology of several neurological diseases.

Footnotes

↵^‡ Recipient of a Studentship from the Fonds de la Recherche en Santé du Québec.
↵* This research was supported by a grant from the Medical Research Council of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

NF

neurofilament

CI

N-acetyl-Leu-Leu-norleucinal

CII

N-acetyl-Leu-Leu-methioninal

DRG

dorsal root ganglia

ERK

extracellular signal-regulated kinase

GST

glutathione S-transferase

MAP

mitogen-activated protein

NFL

NFM, and NFH, low, medium, and high molecular mass neurofilament subunits, respectively

NGF

nerve growth factor

KSP

Lys-Ser-Pro

PAGE

polyacrylamide gel electrophoresis

SAPK

stress-activated protein kinase

TNFα

tumor necrosis factor-α, Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine.
↵² M. G. Sacher, unpublished results.
- Received June 7, 1996.
- Revision received August 15, 1996.