Stretch reflex afferent neurons in human aging and diabetic neuropathy
The loss of tendon reflexes and abnormalities in the gait and movement and balance control are frequent in aged humans and people with diabetes. The atrophy and degeneration of peripheral neurons innervating skeletal muscle stretch (spindle) receptors is a pathogenic mechanism that may lead to these deficiencies. However, the lack of markers for different neuronal pathways limits histological evaluation of stretch receptor afferent pathways in biopsy or autopsy samples of human nerves. To address this question we will utilize recent findings showing that stretch-reflex afferents of vertebrates (including humans) can be specifically identified using immunohistochemical staining for a3 isoform of Na,K-ATPase, the ion transporter maintaining Na and K gradients on the cell membrane (a3 NKA). Our hypothesis is that number of a3 NKA-positive afferent neurons declines in human dorsal root ganglia (DRG) with age and this decline is specifically severe in subjects suffering from distal diabetic somatosensory neuropathies. To address this hypothesis we will study and compare expression of a3 NKA in the samples of human sacral spinal level (S1) DRG obtained from the National Human Tissue Research Center. Samples will be collected post mortem from normal adult human subjects and from subjects with a history of peripheral neuropathy. The a3 NKA will be identified using NKA isoform-specific antibodies. The neuronal density and size distributions will be analyzed and compared among different age groups of subjects and between age-matched groups of control and peripheral neuropathy groups. This work will provide an insight into pathogenesis of movement disorders associated with aging and diabetic neuropathy. It will also provide a basis for studies in animal models of aging and diabetic neuropathy addressing the mechanisms of vulnerability of stretch receptor afferents and evaluating approaches aimed to prevent or ameliorate the loss of these neurons.

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