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Additional file 1: Figure S1. Lysosomal load was not altered in PD patient-derived cells. (A) Representative image and (B) quantification of LAMP1 level (normalized to GAPDH) in whole cell lysates from HS, PD and gPD-GBA N370S cells (n = 13, HS; n = 28, PD; n = 6, gPD-GBA N370S; One-way ANOVA with Tukey’s multiple comparison test). Data represented as mean ± SEM. Figure S2: GCase activity does not correlate with the age of onset or disease duration in PD and gPD-GBA N370S group of cells. Correlation analysis between (A) GCase activity and age of onset (years) and, (B) GCase activity and disease duration (years) was performed in PD and gPD-GBA N370S group of cells and Pearson’s correlation coefficient was determined between the two variables (n = 25, PD; n = 5, gPD-GBA N370S). Figure S3: GRN transcript was reduced in idiopathic PD cells. (A) GRN transcript levels were measured across HS, PD and gPD-GBA N370S cells (n = 13, HS; n = 24, PD; n = 6, gPD-GBA N370S; One-way ANOVA with Tukey’s multiple comparison test, F(2,40) = 4.772, p = 0.0138) using qPCR. (B) Representative image of immunoblot performed using Endo-H and PNGaseF digested lysates from HS, PD and gPD-GBA N370S cells for GBA protein (Quantification in Fig. 2E). Data represented as mean ± SEM. * = p

UNLABELLED: After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly α9β1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a β1-binding integrin activator, kindlin-1. We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6-C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery. SIGNIFICANCE STATEMENT: The study demonstrates that long-distance sensory axon regeneration over a normal pathway and with sensory and sensory-motor recovery can be achieved. This was achieved by expressing an integrin that recognizes tenascin-C, one of the components of glial scar tissue, and an integrin activator. This enabled extensive long-distance (>25 mm) regeneration of both myelinated and unmyelinated sensory axons with topographically correct connections in the spinal cord. The extent of growth and recovery we have seen would probably be clinically significant. Restoration of sensation to hands, perineum, and genitalia would be a significant improvement for a spinal cord-injured patient.