A5070622522- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Metabolism and Genetic Disorders
- Retinal Development and Disorders
- Drug-Induced Ocular Toxicity
- Photosynthetic Processes and Mechanisms
- Genetic Neurodegenerative Diseases
- Cell death mechanisms and regulation
- Cancer, Hypoxia, and Metabolism
- Photoreceptor and optogenetics research
- Circadian rhythm and melatonin
- Retinal Diseases and Treatments
- Glaucoma and retinal disorders
- RNA regulation and disease
- Genetics and Neurodevelopmental Disorders
- Endoplasmic Reticulum Stress and Disease
- Genomics and Rare Diseases
- Coenzyme Q10 studies and effects
- Protein Tyrosine Phosphatases
- Parkinson's Disease Mechanisms and Treatments
- Neurological diseases and metabolism
- Glycogen Storage Diseases and Myoclonus
- Redox biology and oxidative stress
- Ocular Diseases and Behçet’s Syndrome
- RNA modifications and cancer
University of Bologna
2016-2025
Istituto delle Scienze Neurologiche di Bologna
2015-2025
Institute of Neurological Sciences
2016-2025
Istituti di Ricovero e Cura a Carattere Scientifico
2016-2025
Ospedale Bellaria
2013-2024
Azienda USL di Bologna
2023
Massachusetts General Hospital
2023
Medical Research Council
2021
University College London
2020-2021
Moorfields Eye Hospital
2021
Mutations in OPA1, a dynamin-related GTPase involved mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations the OPA1 gene can also be responsible for syndromic form DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external...
Additional neurological features have recently been described in seven families transmitting pathogenic mutations OPA1, the most common cause of autosomal dominant optic atrophy. However, frequency these syndromal 'dominant atrophy plus' variants and extent involvement not established. In this large multi-centre study 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular complications are OPA1 disease, affect up to 20% all mutational carriers. Bilateral...
Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to dysfunction.We assessed nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) 21 mild-moderate AD patients, a subgroup of 16 we evaluated rest-activity rhythm actigraphy. studied postmortem immunohistochemistry retinas, axons optic cross-sections 14...
Dominant optic atrophy (DOA) is characterized by retinal ganglion cell degeneration leading to neuropathy. A subset of DOA caused mutations in the OPA1 gene, encoding for a dynamin-related GTPase required mitochondrial fusion. The functional consequences patients are still poorly understood. This study investigated effect five different pathogenic on energetic efficiency and network dynamics skin fibroblasts from patients. Although maintained their ATP levels grew galactose medium, i.e....
Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as result of homoplasmic point mutations in complex I subunit genes mitochondrial DNA. It characterized by incomplete penetrance, only some mutation carriers become affected. Thus, the DNA necessary but not sufficient to cause neuropathy. Environmental triggers and genetic modifying factors have been considered explain its variable penetrance. We measured copy number mass indicators blood cells from...
Abstract As noted by Warburg, many cancer cells depend on the consumption of glucose. We performed a genetic screen to identify factors responsible for glucose addiction and recovered two subunits xCT antiporter (system x c − ), which plays an antioxidant role exporting glutamate cystine. Disruption greatly improves cell viability after withdrawal, because conservation enables maintain mitochondrial respiration. In some breast cells, expression is upregulated through transcription factor...
An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human atrophy mtDNA ND6 P25L mutation into mouse. Mice with this exhibited reduction in retinal function elecroretinogram (ERG), age-related decline central smaller caliber nerve fibers sparing larger peripheral fibers, neuronal accumulation abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I respiration defects increased reactive oxygen species...
OPA1 is a GTPase that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In humans, eight isoforms are expressed as combinations of long short forms, but it unclear whether functions associated with specific and/or domains. To address this, we each the or different constructs isoform 1 in Opa1−/− MEFs. We observed any could restore structure, abundance, energetic efficiency independently network morphology. Long forms supported fusion; were better able to efficiency....
Leber hereditary optic neuropathy (LHON) is currently estimated as the most frequent mitochondrial disease (1 in 27,000-45,000). Its molecular pathogenesis and natural history now fairly well understood. LHON also first for which a treatment has been approved (idebenone-Raxone, Santhera Pharmaceuticals) by European Medicine Agency, under exceptional circumstances because of rarity severity disease. However, what remains unclear includes optimal target population, timing, dose, frequency...
Dysfunctions in mitochondrial dynamics and metabolism are common pathological processes associated with Parkinson's disease (PD). It was recently shown that an inherited form of PD dementia is caused by mutations the OPA1 gene, which encodes for a key player fusion structure. iPSC-derived neural cells from these patients exhibited severe fragmentation, respiration impairment, ATP deficits, heightened oxidative stress. Reconstitution normal levels PD-derived normalized mitochondria morphology...
At 96 weeks after unilateral intravitreal injection of rAAV2/2- ND4 , vision improved in both eyes 78% subjects affected with LHON.
Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was first to be genetically defined by a point mutation in DNA (mtDNA). A molecular diagnosis achieved up 95% of cases, vast majority which are accounted for 3 mutations within complex I subunit–encoding genes mtDNA (mtLHON). Here, we resolve enigma LHON absence pathogenic mutations. We describe biallelic nuclear encoded gene, DNAJC30, 33 unsolved patients from 29 families establish an autosomal...
PurposeTo evaluate the efficacy of a single intravitreal injection rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).DesignRESCUE is multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.ParticipantsSubjects m.11778G>A mitochondrial DNA mutation and vision ≤6 months onset 1 or both eyes were included.MethodsEach subject’s right eye was randomly assigned (1:1) to treatment (single 9 × 1010 viral genomes 90 μl) sham injection. The...
Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown be effective in stabilizing restoring patients treated within 1 year of onset The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy safety idebenone treatment (900 mg/day) with LHON up 5 years after symptom (N = 199) over period 24 months, compared an external history...
Dysfunction of mitochondrial complex I is a feature human neurodegenerative diseases such as Leber hereditary optic neuropathy and Parkinson's disease. This defect associated with recruitment the mitochondrial-dependent apoptotic pathway in vivo . However, isolated brain mitochondria, dysfunction caused by either pharmacological or genetic means fails to directly activate this cell death pathway. Instead, deficits stimulate intramitochondrial oxidative stress, which, turn, increase...