Fate of Schwann cells in CMT1A and HNPP: evidence for apoptosis.

ABSTRACT

The fate of Schwann cells in Charcot-Marie-Tooth (CMT) neuropathies was addressed in this study of nerve biopsies from patients with proven PMP22 duplications and deletions. In frozen sections, apoptotic nuclei were detected using the TUNEL method. In adjacent sections, anti-neurofilament 68kD antibody was used as an axonal marker, while the antibodies to NKH-1 and low-affinity nerve growth factor receptor P75NTR were used as Schwann cell markers. In addition, plastic sections were used to determine the densities of myelinated fibers and Schwann cell nuclei. In all biopsies from CMT1A, TUNEL-positive nuclei appeared in clusters. In adjacent sections, areas of TUNEL-positive nuclei matched with areas devoid of neurofilaments and NKH-1-positive Schwann cell silhouettes, suggesting that the apoptotic nuclei belonged to nonmyelinating Schwann cells. In addition, quantitative studies on plastic-embedded sections showed a significantly reduced number of total Schwann cells compared with controls, strongly favoring a loss of Schwann cell by apoptosis. In HNPP, the number of total Schwann cells was increased and a significant Schwann cell apoptosis was observed in only 2 patients. Examination of plastic sections and teased nerve preparations from these cases suggested that the Schwann cell apoptosis might be related to the regenerative state of the nerve resulting from the process of sprout pruning. No strict correlation between p75NTR expression and apoptosis was found. These studies indicate that factors regulating Schwann cell number in early postnatal development continue to be important for Schwann cell survival throughout life.