Johns Hopkins University School of Medicine

About: Johns Hopkins University School of Medicine is a healthcare organization based out in Baltimore, Maryland, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 44277 authors who have published 79222 publications receiving 4788882 citations.

Preservation of the Inner Retina in Retinitis Pigmentosa: A Morphometric Analysis

Abstract: Objective: To determine the extent of preservation in the inner retina in retinitis pigmentosa (RP). Methods: We analyzed sectioned maculae of 21 postmortem eyes with RP and 19 age-matched, normal, postmortem eyes. Eyes were divided into 2 groups: severe and moderate RP. Cell nuclei were counted in the outer nuclear, inner nuclear, and ganglion cell layers within thirty 100-μm intervals from the foveola to 1500-μm eccentricity. Results: Statistically significant (P≤.05) loss of both the outer nuclear and ganglion cell layers was present in the groups with moderate and severe RP when compared with the control groups. However, even in the group with severe RP, 30% of the ganglion cells were histologically intact. Similarly, 78% and 88% of the inner nuclear layer cells were preserved in the groups with severe and moderate RP, respectively. Different inheritance modes showed no statistically significant differences in any of the retinal layers. Conclusions: Despite a statistically significant (P≤.05) loss of cells found in all retinal layers, a large percentage of the inner retinal neurons remained histologically intact. Current experimental therapies, such as photoreceptor transplantation and implantation of a visual prosthesis, are based on the premise that some inner retinal neurons are preserved after death of photoreceptors in RP. Our observations support this assumption.

Parkinson's Disease α-Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death

Abstract: α-Synuclein (α-Syn) is enriched in nerve terminals. Two mutations in the α- Syn gene (Ala53→ Thr and Ala30→ Pro) occur in autosomal dominant familial Parkinson9s disease. Mice overexpressing the human A53T mutant α-Syn develop a severe movement disorder, paralysis, and synucleinopathy, but the mechanisms are not understood. We examined whether transgenic mice expressing human wild-type or familial Parkinson9s disease-linked A53T or A30P mutant α-syn develop neuronal degeneration and cell death. Mutant mice were examined at early- to mid-stage disease and at near end-stage disease. Age-matched nontransgenic littermates were controls. In A53T mice, neurons in brainstem and spinal cord exhibited large axonal swellings, somal chromatolytic changes, and nuclear condensation. Spheroid eosinophilic Lewy body-like inclusions were present in the cytoplasm of cortical neurons and spinal motor neurons. These inclusions contained human α-syn and nitrated synuclein. Motor neurons were depleted (∼75%) in A53T mice but were affected less in A30P mice. Axonal degeneration was present in many regions. Electron microscopy confirmed the cell and axonal degeneration and revealed cytoplasmic inclusions in dendrites and axons. Some inclusions were degenerating mitochondria and were positive for humanα-syn. Mitochondrial complex IV and V proteins were at control levels, but complex IV activity was reduced significantly in spinal cord. Subsets of neurons in neocortex, brainstem, and spinal cord ventral horn were positive for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, cleaved caspase-3, and p53. Mitochondria in neurons had terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive matrices and p53 at the outer membrane. Thus, A53T mutant mice develop intraneuronal inclusions, mitochondrial DNA damage and degeneration, and apoptotic-like death of neocortical, brainstem, and motor neurons.

Oxidative stress induces apoptosis in embryonic cortical neurons.

Abstract: Glutamate-induced glutathione depletion in immature embryonic cortical neurons has been shown to lead to oxidative stress and cell death. We have used this in vitro model to investigate the mechanism(s) by which free radicals induce neuronal degeneration. We find that glutathione depletion leads to hyper-condensation and fragmentation of chromatin into spherical or irregular shapes, a morphologic signature of apoptosis. These morphologic changes are accompanied by laddering of DNA into multiple oligonucleosomal fragments and can be prevented by the antioxidants idebenone and butylated hydroxyanisole. Cell death induced by glutathione depletion can also be prevented by inhibitors of macromolecular synthesis. Taken together, these observations suggest that oxidative stress can induce apoptosis in neurons.