Mitochondrial retinopathies

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 com-plex, 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 mito-chondrial 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

Molecular mechanisms behind inherited neurodegeneration of the optic nerve

Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphor-ylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mito-chondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neuro-degeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies

Anticipated Synchronization in a Biologically Plausible Model of Neuronal Motifs

Two identical autonomous dynamical systems coupled in a master-slave configuration can exhibit anticipated synchronization (AS) if the slave also receives a delayed negative self-feedback. Recently, AS was shown to occur in systems of simplified neuron models, requiring the coupling of the neuronal membrane potential with its delayed value. However, this coupling has no obvious biological correlate. Here we propose a canonical neuronal microcircuit with standard chemical synapses, where the delayed inhibition is provided by an interneuron. In this biologically plausible scenario, a smooth transition from delayed synchronization (DS) to AS typically occurs when the inhibitory synaptic conductance is increased. The phenomenon is shown to be robust when model parameters are varied within physiological range. Since the DS-AS transition amounts to an inversion in the timing of the pre- and post-synaptic spikes, our results could have a bearing on spike-timing-dependent-plasticity models

Analysis of ring laser gyroscopes including laser dynamics

Inertial sensors stimulate very large interest, not only for their application but also for fundamental physics tests. Ring laser gyros, which measure angular rotation rate, are certainly among the most sensitive inertial sensors, with excellent dynamic range and bandwidth. Large area ring laser gyros are routinely able to measure fractions of prad/s, with high duty cycle and bandwidth, providing fast, direct and local measurement of relevant geodetic and geophysical signals. Improvements of a factor $10-100$ would open the windows for general relativity tests, as the GINGER project, an Earth based experiment aiming at the Lense-Thirring test at $1\%$ level. However, it is well known that the dynamics of the laser induces non-linearities, and those effects are more evident in small scale instruments. Sensitivity and accuracy improvements are always worthwhile, and in general there is demand for high sensitivity environmental study and development of inertial platforms, where small scale transportable instruments should be used. We discuss a novel technique to analyse the data, aiming at studying and removing those non-linearity. The analysis is applied to the two ring laser prototypes GP2 and GINGERINO, and angular rotation rate evaluated with the new and standard methods are compared. The improvement is evident, it shows that the back-scatter problem of the ring laser gyros is negligible with a proper analysis of the data, improving the performances of large scale ring laser gyros, but also indicating that small scale instruments with sensitivity of nrad/s are feasible.Comment: 9 pages and 7 figure

Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions

Background: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have been associated with variably overlapping phenotypes of Leber’s hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads also to a Leigh-like phenotype. Case presentation: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1 mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6) subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H background, were also present. Conclusion: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the primary LHON mutation

A tunable rf SQUID manipulated as flux and phase qubit

We report on two different manipulation procedures of a tunable rf SQUID. First, we operate this system as a flux qubit, where the coherent evolution between the two flux states is induced by a rapid change of the energy potential, turning it from a double well into a single well. The measured coherent Larmor-like oscillation of the retrapping probability in one of the wells has a frequency ranging from 6 to 20 GHz, with a theoretically expected upper limit of 40 GHz. Furthermore, here we also report a manipulation of the same device as a phase qubit. In the phase regime, the manipulation of the energy states is realized by applying a resonant microwave drive. In spite of the conceptual difference between these two manipulation procedures, the measured decay times of Larmor oscillation and microwave-driven Rabi oscillation are rather similar. Due to the higher frequency of the Larmor oscillations, the microwave-free qubit manipulation allows for much faster coherent operations.Comment: Proceedings of Nobel Symposium "Qubits for future quantum computers", Goeteborg, Sweden, May 25-28, 2009; to appear in Physica Script

OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation.

Hearing impairment is the second most prevalent clinical feature after optic atrophy in Dominant Optic Atrophy associated with mutations in the OPA1 gene. In this study we characterized the hearing dysfunction in OPA1-linked disorders and provided effective rehabilitative options to improve speech perception. We studied two groups of OPA1 subjects, one comprising 11 patients (7 males; age range 13-79 years) carrying OPA1 mutations inducing haploinsufficiency, the other, 10 subjects (3 males; age range 5-58 years) carrying OPA1 missense mutations. Both groups underwent audiometric assessment with pure tone and speech perception evaluation, and otoacoustic emissions and auditory brainstem response recording. Cochlear potentials were recorded through transtympanic electrocochleography from the group of patients harboring OPA1 missense mutations and were compared to recordings obtained from 20 normally-hearing controls and from 19 subjects with cochlear hearing loss. Eight patients carrying OPA1 missense mutations underwent cochlear implantation. Speech perception measures and electrically-evoked auditory nerve and brainstem responses were obtained after one year of cochlear implant use. Nine out of 11 patients carrying OPA1 mutations inducing haploinsufficiency had normal hearing function. In contrast, all but one subject harboring OPA1 missense mutations displayed impaired speech perception, abnormal brainstem responses and presence of otoacoustic emissions consistent with auditory neuropathy. In electrocochleography recordings, cochlear microphonic had enhanced amplitudes while summating potential showed normal latency and peak amplitude consistent with preservation of both outer and inner hair cell activities. After cancelling the cochlear microphonic, the synchronized neural response seen in both normally-hearing controls and subjects with cochlear hearing loss was replaced by a prolonged, low-amplitude negative potential that decreased in both amplitude and duration during rapid stimulation consistent with neural generation. The use of cochlear implant improved speech perception in all but one patient. Brainstem potentials were recorded in response to electrical stimulation in five subjects out of six, whereas no compound action potential was evoked from the auditory nerve through the cochlear implant. These findings indicate that underlying the hearing impairment in patients carrying OPA1 missense mutations is a disordered synchrony in auditory nerve fiber activity resulting from neural degeneration affecting the terminal dendrites. Cochlear implantation improves speech perception and synchronous activation of auditory pathways by by-passing the site of lesion