S. Samantaray and V. Knaryan contributed equally to this study.
Critical role of calpain in spinal cord degeneration in Parkinson's disease
Article first published online: 20 AUG 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 127, Issue 6, pages 880–890, December 2013
How to Cite
J. Neurochem.(2013) 127, 880–890.
- Issue published online: 3 DEC 2013
- Article first published online: 20 AUG 2013
- Accepted manuscript online: 22 JUL 2013 06:20AM EST
- Manuscript Accepted: 5 JUL 2013
- Manuscript Revised: 26 JUN 2013
- Manuscript Received: 11 MAY 2013
- National Institute of Neurological Disorders Stroke of the National Institutes of Health. Grant Numbers: NS-62327-01A2, NS-56176, NS-65456
- Veterans Administration. Grant Number: I01 BX001262
- axonal degeneration;
While multiple molecular mechanisms contribute to midbrain nigrostriatal dopaminergic degeneration in Parkinson's disease (PD), the mechanism of damage in non-dopaminergic sites within the central nervous system, including the spinal cord, is not well-understood. Thus, to understand the comprehensive pathophysiology underlying this devastating disease, postmortem spinal cord tissue samples (cervical, thoracic, and lumbar segments) from patients with PD were analyzed compared to age-matched normal subjects or Alzheimer's disease for selective molecular markers of neurodegeneration and inflammation. Distal axonal degeneration, relative abundance of both sensory and motor neuron death, selective loss of ChAT+ motoneurons, reactive astrogliosis, microgliosis, increased cycloxygenase-2 (Cox-2) expression, and infiltration of T cells were observed in spinal cord of PD patients compared to normal subjects. Biochemical analyses of spinal cord tissues revealed associated inflammatory and proteolytic events (elevated levels of Cox-2, expression and activity of μ- and m-calpain, degradation of axonal neurofilament protein, and concomitantly low levels of endogenous inhibitor – calpastatin) in spinal cord of PD patients. Thus, pathologically upregulated calpain activity in spinal cords of patients with PD may contribute to inflammatory response-mediated neuronal death, leading to motor dysfunction.
We proposed calpain over-activation and calpain-calpastatin dysregulation driving in a cascade of inflammatory responses (microglial activation and T cell infiltration) and degenerative pathways culminating in axonal degeneration and neuronal death in spinal cord of Parkinson's disease patients. This may be one of the crucial mechanisms in the degenerative process.