SCG10 is a JNK target in the axonal degeneration pathway.

Axons actively self-destruct following genetic, mechanical, metabolic, and toxic insults, but the mechanism of axonal degeneration is poorly understood. The JNK pathway promotes axonal degeneration shortly after axonal injury, hours before irreversible axon fragmentation ensues. Inhibition of JNK activity during this period delays axonal degeneration, but critical JNK substrates that facilitate axon degeneration are unknown. Here we show that superior cervical ganglion 10 (SCG10), an axonal JNK substrate, is lost rapidly from mouse dorsal root ganglion axons following axotomy. SCG10 loss precedes axon fragmentation and occurs selectively in the axon segments distal to transection that are destined to degenerate. Rapid SCG10 loss after injury requires JNK activity. The JNK phosphorylation sites on SCG10 are required for its rapid degradation, suggesting that direct JNK phosphorylation targets SCG10 for degradation. We present a mechanism for the selective loss of SCG10 distal to the injury site. In healthy axons, SCG10 undergoes rapid JNK-dependent degradation and is replenished by fast axonal transport. Injury blocks axonal transport and the delivery of SCG10, leading to the selective loss of the labile SCG10 distal to the injury site. SCG10 loss is functionally important: Knocking down SCG10 accelerates axon fragmentation, whereas experimentally maintaining SCG10 after injury promotes mitochondrial movement and delays axonal degeneration. Taken together, these data support the model that SCG10 is an axonal-maintenance factor whose loss is permissive for execution of the injury-induced axonal degeneration program.

Structure and clinical significance of central optic disc pits.

OBJECTIVE: To assess the structure of central optic disc pits (ODPs) using enhanced-depth imaging optical coherence tomography (EDI OCT) and to ascertain their clinical significance. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with an ophthalmoscopically visible central ODP in either eye, irrespective of accompanying ocular disease, were enrolled from the neuro-ophthalmology and glaucoma referral practices. Each subject with a central ODP was matched with 2 healthy subjects with normal-appearing optic disc within 5 years of age. METHODS: Each participant received a complete ophthalmologic examination including standard automated perimetry, retinal nerve fiber layer (RNFL) thickness measurement by OCT, and serial horizontal and vertical cross-sectional EDI OCT of the optic nerve head. MAIN OUTCOME MEASURES: Structure of the lamina cribrosa (LC) in relation to the central ODP in EDI OCT images. RESULTS: Eighteen eyes (13 subjects) with a central ODP and 52 healthy eyes (26 controls) were included. Four eyes (2 subjects) with a central ODP were otherwise normal with intact macula, neuroretinal rim, RNFL, and visual field. Fourteen eyes (11 subjects) with a central ODP had glaucoma with glaucomatous neuroretinal rim thinning, RNFL loss, and corresponding visual field defect. No eye had associated maculopathy. On EDI OCT, the central ODP corresponded with a full-thickness defect in the LC center with no serous retinal detachment or herniation of neural tissue through the LC defect. Central ODPs were separated from (type 1) or merged with (type 2) the LC opening for the central retinal vascular trunk. In control eyes, no LC defect was detected. CONCLUSIONS: Central ODPs are full-thickness LC defects unassociated with maculopathy and different from glaucomatous acquired pits of the optic nerve, which represent focal laminar defect adjacent to the disc edge.

Enhanced depth imaging optical coherence tomography of optic nerve head drusen.

OBJECTIVE: To assess the value of enhanced depth imaging optical coherence tomography (EDI OCT) in diagnosing and evaluating optic nerve head drusen (ONHD) compared with conventional diagnostic methods. DESIGN: Prospective, comparative, cross-sectional study. PARTICIPANTS: Thirty-four patients with clinically visible or suspected ONHD in either eye based on dilated optic disc examination or optic disc stereophotography and without ocular comorbidity. METHODS: Spectral-domain OCT of the optic nerve head in both conventional (non-EDI) and EDI modes, ultrasound B-scan, and standard automated perimetry were performed on both eyes of all participants. MAIN OUTCOME MEASURES: Detection and findings of ONHD between EDI OCT and conventional diagnostic methods. RESULTS: Sixty-eight eyes were clinically classified into 3 groups: 32 eyes with definite ONHD, 25 eyes with suspected ONHD, and 11 normal-appearing fellow eyes. In the definite ONHD group, EDI OCT, non-EDI OCT, and ultrasound B-scan were positive for ONHD in all eyes and visual field (VF) was abnormal in 24 eyes. In the suspected ONHD group, EDI OCT, non-EDI OCT, ultrasound B-scan, and VF were positive in 17, 14, 7, and 3 eyes, respectively; 8 eyes had no evidence of ONHD in any of the tests. In normal-appearing fellow eyes, EDI OCT, non-EDI OCT, ultrasound B-scan, and VF were positive in 3, 1, 1, and 0 eyes, respectively; 4 eyes had no evidence of ONHD in any of the tests. Enhanced depth imaging OCT had a significantly higher ONHD detection rate than ultrasound B-scan in all eyes (52/68 eyes vs. 40/68 eyes; P<0.001), in eyes with clinically suspected ONHD or normal-appearing fellow eyes (20/36 eyes vs. 8/36 eyes; P<0.001), and in eyes with clinically suspected ONHD (17/25 eyes vs. 7/25 eyes; P = 0.002). Enhanced depth imaging OCT-detected ONHD appeared as signal-poor regions surrounded by short, hyper-reflective bands or isolated/clustered hyper-reflective bands without a signal-poor core. In non-EDI OCT, posterior surfaces of the ONHD and deep-seated hyper-reflective bands were invisible or less clear than in EDI OCT. CONCLUSIONS: Enhanced depth imaging OCT detects lesions likely representing ONHD more often and better assesses their shape and structure than conventional tests.