Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Maresca, Alessandra; Carelli, Valerio

doi:10.3390/biom11040496

Cited by 12 publications

(6 citation statements)

References 300 publications

(232 reference statements)

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“…Recent reports further highlighted the adjunctive occurrence of rod-cone dystrophy associated with optic atrophy in RN4IP1 patients [ 163 , 164 ]. Remarkably, patients’ fibroblasts show mitochondrial network fragmentation and respiratory cI disassembly, bridging the known optic atrophy-related pathogenic mechanisms and prompting further investigations to disentangle how MAM, cI and mitochondrial dynamics converge physiologically and lead to disease when impaired [ 165 ].…”

Section: Rare Mitochondrial Causes Of Optic Atrophymentioning

confidence: 99%

Mitochondrial Retinopathies

Zeviani

Carelli

2021

IJMS

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The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns–Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29.

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Section: Rare Mitochondrial Causes Of Optic Atrophymentioning

confidence: 99%

Mitochondrial Retinopathies

Zeviani

Carelli

2021

IJMS

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“…Moreover, in the myelinated portion of the optic nerve a wide variability of myelin thickness is also evident, with some axons being almost denuded of myelin sheath. In some cases, evidence of remyelination has been recognized, suggesting a dynamic physiopathological process rather than simply neurodegeneration [ 3 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Multishell Diffusion MR Tractography Yields Morphological and Microstructural Information of the Anterior Optic Pathway: A Proof-of-Concept Study in Patients with Leber’s Hereditary Optic Neuropathy

Manners

Gramegna

Morgia

et al. 2022

IJERPH

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Tractography based on multishell diffusion-weighted magnetic resonance imaging (DWI) can be used to estimate the course of myelinated white matter tracts and nerves, yielding valuable information regarding normal anatomy and variability. DWI is sensitive to the local tissue microstructure, so tractography can be used to estimate tissue properties within nerve tracts at a resolution of millimeters. This study aimed to test the applicability of the method using a disease with a well-established pattern of myelinated nerve involvement. Eight patients with LHON and 13 age-matched healthy controls underwent tractography of the anterior optic pathway. Diffusion parameters were compared between groups, and for the patient group correlated with clinical/ophthalmological parameters. Tractography established the course of the anterior optic pathway in both patients and controls. Localized changes in fractional anisotropy were observed, and related to estimates of different tissue compartments within the nerve and tract. The proportion of different compartments correlated with markers of disease severity. The method described allows both anatomical localization and tissue characterization in vivo, permitting both visualization of variation at the individual level and statistical inference at the group level. It provides a valuable adjunct to ex vivo anatomical and histological study of normal variation and disease processes.

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“…We therefore do not include discussion on genes that cause optic atrophy as a feature of another neurological disorder such as NDUFS2 (primarily associated with Leigh syndrome) ( Gerber et al, 2017a ), SPG7 (primarily associated with HSP) ( Charif et al, 2020 ), CISD2 (primarily associated with Wolfram syndrome) ( Delprat et al, 2018 ), C19orf12 (primarily associated with MPAN syndrome) ( Mignani et al, 2020 ) or MFN2 (primarily associated with CMT2) ( Bombelli et al, 2014 ). The role of many of these genes in mitochondrial function has been recently reviewed elsewhere ( Maresca and Carelli, 2021 ).…”

Section: Gene Mutations Causing Autosomal Optic Atrophymentioning

confidence: 99%

The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance

et al. 2021

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Optic atrophy (OA) with autosomal inheritance is a form of optic neuropathy characterized by the progressive and irreversible loss of vision. In some cases, this is accompanied by additional, typically neurological, extra-ocular symptoms. Underlying the loss of vision is the specific degeneration of the retinal ganglion cells (RGCs) which form the optic nerve. Whilst autosomal OA is genetically heterogenous, all currently identified causative genes appear to be associated with mitochondrial organization and function. However, it is unclear why RGCs are particularly vulnerable to mitochondrial aberration. Despite the relatively high prevalence of this disorder, there are currently no approved treatments. Combined with the lack of knowledge concerning the mechanisms through which aberrant mitochondrial function leads to RGC death, there remains a clear need for further research to identify the underlying mechanisms and develop treatments for this condition. This review summarizes the genes known to be causative of autosomal OA and the mitochondrial dysfunction caused by pathogenic mutations. Furthermore, we discuss the suitability of available in vivo models for autosomal OA with regards to both treatment development and furthering the understanding of autosomal OA pathology.

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Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Cited by 12 publications

References 300 publications

Mitochondrial Retinopathies

Mitochondrial Retinopathies

Multishell Diffusion MR Tractography Yields Morphological and Microstructural Information of the Anterior Optic Pathway: A Proof-of-Concept Study in Patients with Leber’s Hereditary Optic Neuropathy

The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance

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