Craig Pearson

Program: Unspecified

Current advisor:

Undergraduate university: Michigan State University

Research summary
The failure of mammalian CNS neurons to regenerate their axons derives from a combination of intrinsic deficits and extrinsic obstacles. Following injury, chondroitin sulfate proteoglycans (CSPGs) accumulate within the glial scar that forms at the lesion site in response to the insult. CSPGs inhibit axonal growth and regeneration, an action mediated by their sulfated glycosaminoglycan (GAG) chains, especially those with 4-sulfated (4S) sugars. Arylsulfatase B (ARSB) selectively cleaves 4S groups from the non-reducing ends of GAG chains without disrupting other, potentially growth-permissive motifs. In this thesis, I determine the time course and spatial distribution of CSPG accumulation in the glial scar following acute injury, and then demonstrate that ARSB is effective in reducing the inhibitory actions of CSPGs. I examine the effects of ARSB in an in vitro model of the glial scar and in vivo, using optic nerve crush (ONC) in adult mice. ARSB is clinically approved for replacement therapy in patients with mucopolysaccharidosis VI and therefore represents an attractive candidate for translation to the human CNS. My findings illustrate the importance of CSPGs as a barrier to axon extension following injury, and show compelling evidence that selective modification of the sulfation pattern on GAG chains results in significant enhancement of RGC axonal regeneration. Finally, I combine ARSB treatment with a host of intrinsic pro-regenerative stimuli and show robust, long-distance regeneration of RGC axons through the optic chiasm and into the optic tract. Taken together, the results of this thesis argue for the therapeutic potential of modifying the extracellular matrix to promote regeneration of axons in the CNS.

Graduate publications
Petrova V, Pearson CS, Ching J, Tribble JR, Solano AG, Yang Y, Love FM, Watt RJ, Osborne A, Reid E, Williams PA, Martin KR, Geller HM, Eva R, Fawcett JW. 2022 Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat Commun, 11(1):5614.

Pearson C, Siegel J, Gold JA.. 2022 Psilocybin-assisted psychotherapy for depression: Emerging research on a psychedelic compound with a rich history. J Neurol Sci, 434():120096.

Nagase H, Higashi SL, Iweka CA, Pearson CS, Hirata Y, Geller HM, Katagiri Y. 2021 Reliable and sensitive detection of glycosaminoglycan chains with immunoblots. Glycobiology, 31(2):116-125.

Pearson CS, Solano AG, Tilve SM, Mencio CP, Martin KR, Geller HM. 2020 Spatiotemporal distribution of chondroitin sulfate proteoglycans after optic nerve injury in rodents. Exp Eye Res, 190():107859.

Higashi SL, Yagyu K, Nagase H, Pearson CS, Geller HM, Katagiri Y. 2020 Ultra-High-Speed Western Blot using Immunoreaction Enhancing Technology. J Vis Exp, (163):10.3791/61657.

Nieuwenhuis B, Barber AC, Evans RS, Pearson CS, Fuchs J, MacQueen AR, van Erp S, Haenzi B, Hulshof LA, Osborne A, Conceicao R, Khatib TZ, Deshpande SS, Cave J, Ffrench-Constant C, Smith PD, Okkenhaug K, Eickholt BJ, Martin KR, Fawcett JW, Eva R. 2020 PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS. EMBO Mol Med, 12(8):e11674.