Molecular Mechanisms of Programmed Cell Death in Human Cervical Spondylotic Myelopathy

Michael G. Fehlings, MD, PhD,
Wenru Yu, MD,
Patrick Shannon, MD (Toronto, ON)

Introduction:

Although cervical spondylotic myelopathy (CSM) is a leading cause of spinal cord dysfunction, the molecular mechanisms of neural degeneration remain unclear. Given that apoptosis or genetically programmed cell death contributes to the pathophysiology of neural ischemia and trauma, we hypothesized that apoptosis plays a key role in CSM.

Methods:

Sections of post–mortem cervical cord tissue from 8 patients with CSM (6M, 2F: mean age 73, range 61–89) and three control spinal cords were stained with hematoxylin–eosin/luxol fast blue and examined for apoptosis by the TUNEL technique. Double labelling with cell specific markers (GFAP MAP2, NF200, myelin basic protein and CD68) was undertaken to identify astrocytes, neurons, axons,
oligodendrocytes and microglia respectively. Expression of activated caspase–3, the FAS "death" receptor and the P75 neurotrophin receptor were examined by immunohistochemistry.

Results:

There was prominent anterior horn cell loss, dorsal root degeneration, and extensive loss of myelinated axons particularly in the dorsal and lateral columns. Numerous TUNEL positive cells (x= 179.2 +/– 26.5) were seen in the dorsal and lateral columns. Caspase–3 and P75 were expressed in neurons and degenerating axons. FAS was present predominantly in oligodendrocytes. Extensive oligodendroglial apoptosis was observed in association with axonal degradation. CONCLUSIONS: This is the first study to demonstrate that apoptosis of neurons and oligodendrocytes occurs in human CSM. FAS and p75 receptor activation may turn on the caspase–3 cell death pathway in CSM . Early surgical intervention, neuroprotective approaches, or gene therapy may attenuate this form of genetically programmed cell death.