Dataset Information

Abnormal large-scale structural rich club organization in Leber's hereditary optic neuropathy.

ABSTRACT:

Objective

The purpose of this study was to investigate whether the large-scale structural rich club organization was abnormal in patients with Leber's hereditary optic neuropathy (LHON) using diffusion tensor imaging (DTI), and the associations among disrupted brain structural connectivity, disease duration, and neuro-ophthalmological impairment.

Methods

Nineteen acute, 34 chronic LHON patients, and 36 healthy controls (HC) underwent DTI and neuro-ophthalmological measurements. The brain structural network and rich club organization were constructed based on deterministic fiber tracking at the individual level. Then intergroup differences among the acute, chronic LHON patients and healthy controls (HC) in three types of structural connections, including rich club, feeder, and local ones, were compared. Network-based Statistics (NBS) was also used to test the intergroup connectivity differences for each fiber. Several linear and nonlinear curve fit models were applied to explore the associations among large-scale brain structural connectivity, disease duration, and neuro-ophthalmological metrics.

Results

Compared to the HC, both the acute and chronic LHON patients had consistently significantly lower fractional anisotropy (FA) and higher radial diffusion (RD) for feeder connections (p < 0.05, FDR correction). Acute LHON patients had significantly lower FA and higher RD for local connections (p < 0.05, FDR correction). There was no significant difference in large-scale brain structural connectivity between acute and chronic LHON (p > 0.05, FDR correction). NBS also identified reduced FA of three feeder connections and five local ones linking visual, auditory, and basal ganglia areas in LHON patients (p < 0.05, FDR correction). No structural connections showed linear or nonlinear association with either disease duration or neuro-ophthalmological indicators (p > 0.05, FDR correction). A significant negative correlation was shown between the retinal nerve fiber layer (RNFL) thickness and disease duration (p < 0.05, FDR correction).

Conclusions

Abnormal rich club organization of the structural network was identified in both the acute and chronic LHON. Furthermore, our findings suggest the coexistence of both primary and secondary connectivity damage in the LHON.

SUBMITTER: Zhang J

PROVIDER: S-EPMC8010853 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Leber's hereditary optic neuropathy (LHON, MIM#535000) is the most common form of inherited optic neuropathies and mitochondrial DNA-related diseases. The pathogenicity of mutations in genes encoding components of mitochondrial Complex I is well established, but the underlying pathomechanisms of the disease are still unclear. Hypothesizing that oxidative stress related to Complex I deficiency may increase protein S-glutathionylation, we investigated the proteome-wide S-glutathionylation profiles in LHON (n = 11) and control (n = 7) fibroblasts, using the GluICAT platform that we recently developed. Glutathionylation was also studied in healthy fibroblasts (n = 6) after experimental Complex I inhibition. The significantly increased reactive oxygen species (ROS) production in the LHON group by Complex I was shown experimentally. Among the 540 proteins which were globally identified as glutathionylated, 79 showed a significantly increased glutathionylation (p < 0.05) in LHON and 94 in Complex I-inhibited fibroblasts. Approximately 42% (33/79) of the altered proteins were shared by the two groups, suggesting that Complex I deficiency was the main cause of increased glutathionylation. Among the 79 affected proteins in LHON fibroblasts, 23% (18/79) were involved in energetic metabolism, 31% (24/79) exhibited catalytic activity, 73% (58/79) showed various non-mitochondrial localizations, and 38% (30/79) affected the cell protein quality control. Integrated proteo-metabolomic analysis using our previous metabolomic study of LHON fibroblasts also revealed similar alterations of protein metabolism and, in particular, of aminoacyl-tRNA synthetases. S-glutathionylation is mainly known to be responsible for protein loss of function, and molecular dynamics simulations and 3D structure predictions confirmed such deleterious impacts on adenine nucleotide translocator 2 (ANT2), by weakening its affinity to ATP/ADP. Our study reveals a broad impact throughout the cell of Complex I-related LHON pathogenesis, involving a generalized protein stress response, and provides a therapeutic rationale for targeting S-glutathionylation by antioxidative strategies.

Project description:PURPOSE: To screen mitochondrial DNA (mtDNA) variations in Leber hereditary optic neuropathy (LHON). METHODS: Ten LHON patients were selected from neuro-ophthalmology clinics of All India Institute of Medical Sciences (AIIMS), New Delhi, India. Clinical evaluation included slit-lamp biomicroscopy, fundus examination, and neuroimaging. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in ten patients and 20 controls. The full mtDNA genome except D-loop was sequenced. All sequences were analyzed against mitochondrial reference sequence NC_012920. RESULTS: MtDNA sequencing revealed a total of 30 nucleotide variations in the ten LHON patients and 29 in the 20 controls. Of 30 changes, 30.00% (9/30) were nonsynonymous, and the remaining 70.00% (21/30) were synonymous. In controls, a total of five changes were nonsynonymous. Out of the total 14 nonsynonymous changes observed in cases and controls, four (p.A52T in nicotinamide adenine dinucleotide [NADH] dehydrogenase [ND1] protein; p.L128Q in ND2; p.W48R in ATPase6; p.R340H in ND4 protein) were pathogenic. Four patients were positive for either of pathogenic changes. In total, 16.66% (5/30) variations were novel out of which 40.00% (2/5) were nonsynonymous. All novel variations were submitted to the GenBank database, and accession numbers were obtained. Primary LHON mutations in complex I genes have been considered a hallmark feature of LHON patients, and primary LHON mutations were present in two cases in this study. Mutations in complex I genes (ND genes) account for 50%-90% of LHON pedigrees in different ethnic pedigrees. In this study the highest numbers of changes were also present in complex I genes (46.66%; 14/30) followed by complex IV (30.00%; 9/30), complex III (16.66%; 5/30), and then complex V (6.66%; 2/30). Complex I had 5/30 (16.66%) nonsynonymous changes, complex III had 1/30 (3.33%), complex IV had 1/30 (3.33%), and complex V had 2/30 (6.66%) nonsynonymous changes. Nonsynonymous mutations in cytochrome c oxidase (COX) genes have been reported previously in LHON patients. Nonsynonymous mtDNA variations may adversely affect the respiratory chain and impair the oxidative phosphorylation (OXPHOS) pathway, resulting in low ATP production and elevated reactive oxygen species (ROS) levels, which cause oxidative stress. It has previously been reported that oxidative stress (OS) leads to oxidative damage of cellular macromolecules, such as mitochondrial and nuclear DNA, proteins, and lipids along with energy depletion and a local imbalance of calcium homeostasis, resulting in neuronal degeneration. OS is the underlying etiology in several ocular diseases and also plays an essential role in LHON. CONCLUSIONS: A total of five novel mtDNA variations were identified in this study. Nonsynonymous mtDNA variations may adversely affect the respiratory chain and impair the OXPHOS pathway, resulting in low ATP production and elevated ROS levels. OS further damages both nuclear and mtDNA. This preliminary study describes mtDNA sequence variations in a relatively small number of LHON patients of north Indian ethnic origin. However, these results should be confirmed in other populations. Early diagnosis of mtDNA variations and prompt anti-oxidant administration in these cases may delay OS-induced injury to retinal ganglion cells (RGCs) and hence improve visual prognosis.