Poster abstracts

Poster number 93 submitted by Patrick Heilman

Consequences of Axonal Neuropathy Associated HSPB1 Mutations on NF-kB Stress Signaling Paithways

Patrick L. Heilman (Ohio State Biochemistry Program), Stephen J. Kolb MD., PhD (Molecular and Cellular Biochemistry, OSU.)

Abstract:
Neuroinflammation plays a key role in the pathogenesis of many diseases, including Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s Disease (AD) and Multiple Sclerosis. One of the major signaling pathways of the neuroinflammatory response is the Nuclear Factor Kappa Beta (NF-κβ) pathway, which regulates the expression of pro and anti-inflammatory cytokines. The small heat shock protein 27 (HSPB1) is a molecular chaperone that displays neuroprotective properties in many disease and injury models [1, 2]. Mutations in HSPB1 result in a late-onset distal axonal neuropathy (dHMN) [3, 4]. HSPB1 regulates the activation of NF-κβ signaling by interacting with multiple upstream protein complexes. Here, we investigated how dHMN causing mutations in HSPB1 affect the NF- κβ pathway. In HeLa cells, overexpression of HSPB1 reduces TNFα-mediated NF-κβ by binding IKKβ and downregulating its activity [5]. We confirmed these results in our lab, and have found that a dHMN-associated mutation in HSPB1 is defective in its ability to alter NF-κβ signaling.

References:
1. Read, D.E. and A.M. Gorman, Heat shock protein 27 in neuronal survival and neurite outgrowth. Biochem Biophys Res Commun, 2009. 382(1): p. 6-8.
2. Sharp, P., et al., Heat shock protein 27 rescues motor neurons following nerve injury and preserves muscle function. Exp Neurol, 2006. 198(2): p. 511-8.
3. Evgrafov, O.V., et al., Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet, 2004. 36(6): p. 602-6.
4. Houlden, H., et al., Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2. Neurology, 2008. 71(21): p. 1660-8.
5. Park, K.J., R.B. Gaynor, and Y.T. Kwak, Heat shock protein 27 association with the I kappa B kinase complex regulates tumor necrosis factor alpha-induced NF-kappa B activation. J Biol Chem, 2003. 278(37): p. 35272-8.

Keywords: HSPB1, Axonal Neuropathy, NF-kB