Recombinant Human Persephin Protein

Persephin is a secreted protein belonging to the glial cell line-derived neurotrophic factor (GDNF) family of the TGF-beta superfamily. It shares 38 - 46% amino acid (aa) identity with family members GDNF, neurturin and artemin. Persephin is expressed at very low levels in most tissues (1). The 156 aa, 10 - 12 kDa mature protein contains a signal sequence, a pro-domain and a 96 aa mature sequence with several cysteines that are conserved among family members. It circulates as an unglycosylated disulfide-linked homodimer. Mature human Persephin shares 81% and 80%, 89% and 87% amino acid sequence identity with mouse, rat, bovine and canine Persephin, respectively. Like other GDNF family members, Persephin acts through engagement of GRF alpha 4, a glycosylphosphatidylinositol (GPI)-linked GDNF receptor family (GRF) member that signals through the receptor tyrosine kinase RET. Persephin is reported to promote both the survival and growth of central dopaminergic and motor neurons, and kidney development (1). These effects are correlated with the expression patterns of GFR alpha 4, and RET (2, 3). Functional GFR alpha 4 isoforms are found only in thyroid, adrenal medulla and portions of the central nervous system, and include GPI-linked, transmembrane and soluble forms (3, 4). In vitro, Persephin promotes survival only in neurons which coexpress GPI-linked GFR alpha 4 with RET (2, 5). This effect does not show a strong correlation to the recruitment of RET in lipid rafts seen with other GDNF family members (6). Disruption of the Persephin gene results in mice that are morphologically normal but have more damage and less effective repair after central nervous system insult that stimulates a stroke. Microinjection of Persephin prior to treatment protects against damage in both wild-type and mutant mouse brains, but surprisingly, high doses of Persephin are detrimental (7).