Overexpression of human HSP27 protects sensory neurons from diabetes.

Diabetic polyneuropathy (DPN) may be among the most common neurodegenerative disorders, involving approximately 50% of all persons with diabetes mellitus, now ranked at 6–10% of the global population and rising in prevalence (Wild et al., 2004; Yang et al., 2010). The mechanisms of DPN remain uncertain and the disorder is currently irreversible. Roles for excessive polyol flux, nerve microangiopathy, impaired growth factor availability and free radical stress, among others, have all been considered (Obrosova, 2008; Tomlinson, 2008; Zochodne, 2007). While controversial, a common thread among these ideas is that there is neuronal targeting by a unique and gradual neurodegenerative cascade that involves sensory neurons early. If correct, an approach that augments intrinsic survival pathways would prevent the range of abnormalities that develop during neuropathy in the peripheral nervous system. Heat shock proteins (HSPs) are candidates for protecting sensory neurons from neurotoxic insults. As inducible molecular chaperones, they assist in the proper folding and assembly of nascent polypeptides and help to target abnormal proteins for lysosomal degradation (Ohtsuka and Suzuki, 2000). HSPs provide constitutive protection to peripheral neurons, since HSP27 gene mutations, for example, are associated with inherited forms of polyneuropathy (Houlden et al., 2008). An association between the presence of polyneuropathy and circulating HSP27 has also been identified in a large cohort of human subjects with type 1 diabetes mellitus (Gruden et al., 2008). HSP27 expression promotes survival of adult sensory and motor neurons after axonal injury, and its expression is elevated in sensory neurons of diabetic rodent models (Benn et al., 2002; Zochodne et al., 2001). HSP27 (or its mouse analog, HSP25) knockdown or overexpression are respectively associated with attenuated or improved axon regeneration in adult sensory neurons (Lewis et al., 1999; Ma et al., in press). We hypothesized that overexpression of a human transgene of HSP27 in mice rendered Type 1 diabetic with streptozotocin (STZ) might protect peripheral neurons from progressive degeneration. The findings identified an interesting form of apparent selective sensory neuron protection over a range of behavioral, electrophysiological, structural and molecular neuropathic abnormalities.