A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction.

Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which there are currently no disease-modifying therapies. Previous studies suggest inhibitory interneuron susceptibility to mitochondrial impairment, especially of parvalbumin-expressing interneurons (PV). We have developed a mouse model of mitochondrial dysfunction specifically in PV cells via conditional Tfam knockout, that exhibited a juvenile-onset progressive phenotype characterised by cognitive deficits, anxiety-like behaviour, head-nodding, stargazing, ataxia, and reduced lifespan.

Astrocytic pathology in Alpers' syndrome.

Refractory epilepsy is the main neurological manifestation of Alpers' syndrome, a severe childhood-onset mitochondrial disease caused by bi-allelic pathogenic variants in the mitochondrial DNA (mtDNA) polymerase gamma gene (POLG). The pathophysiological mechanisms underpinning neuronal hyperexcitabilty leading to seizures in Alpers' syndrome remain unknown. However, pathological changes to reactive astrocytes are hypothesised to exacerbate neural dysfunction and seizure-associated cortical activity in POLG-related disease.

Delineating selective vulnerability of inhibitory interneurons in Alpers' syndrome.

Aims: Alpers' syndrome is a severe neurodegenerative disease typically caused by bi-allelic variants in the mitochondrial DNA (mtDNA) polymerase gene, POLG, leading to mtDNA depletion. Intractable epilepsy, often with an occipital focus, and extensive neurodegeneration are prominent features of Alpers' syndrome. Mitochondrial oxidative phosphorylation (OXPHOS) is severely impaired with mtDNA depletion and is likely to be a major contributor to the epilepsy and neurodegeneration in Alpers' syndrome.

Forecasting stroke-like episodes and outcomes in mitochondrial disease.

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource.

Complex I reductions in the nucleus basalis of Meynert in Lewy body dementia: the role of Lewy bodies.

Neurons of the nucleus basalis of Meynert (nbM) are vulnerable to Lewy body formation and neuronal loss, which is thought to underlie cognitive dysfunction in Lewy body dementia (LBD). There is continued debate about whether Lewy bodies exert a neurodegenerative effect by affecting mitochondria, or whether they represent a protective mechanism. Therefore, the present study sought to determine whether the nbM is subject to mitochondrial dysfunctional in LBD and the association of Lewy body formation with such changes.

The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction.

Approximately one-quarter of patients with mitochondrial disease experience epilepsy. Their epilepsy is often severe and resistant towards conventional antiepileptic drugs. Despite the severity of this epilepsy, there are currently no animal models available to provide a mechanistic understanding of mitochondrial epilepsy.

mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect.

OXA1, the mitochondrial member of the YidC/Alb3/Oxa1 membrane protein insertase family, is required for the assembly of oxidative phosphorylation complexes IV and V in yeast. However, depletion of human OXA1 (OXA1L) was previously reported to impair assembly of complexes I and V only. We report a patient presenting with severe encephalopathy, hypotonia and developmental delay who died at 5 years showing complex IV deficiency in skeletal muscle.

Dissecting the neuronal vulnerability underpinning Alpers' syndrome: a clinical and neuropathological study.

Alpers' syndrome is an early-onset neurodegenerative disorder often caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG) which is essential for mitochondrial DNA (mtDNA) replication. Alpers' syndrome is characterized by intractable epilepsy, developmental regression and liver failure which typically affects children aged 6 months-3 years. Although later onset variants are now recognized, they differ in that they are primarily an epileptic encephalopathy with ataxia.

MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.

Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers.

The genetics and pathology of mitochondrial disease.

Mitochondria are double-membrane-bound organelles that are present in all nucleated eukaryotic cells and are responsible for the production of cellular energy in the form of ATP. Mitochondrial function is under dual genetic control - the 16.6-kb mitochondrial genome, with only 37 genes, and the nuclear genome, which encodes the remaining ∼1300 proteins of the mitoproteome.

Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations.

Dementia with Lewy bodies (DLB) patients frequently experience well formed recurrent complex visual hallucinations (RCVH). This is associated with reduced blood flow or hypometabolism on imaging of the primary visual cortex. To understand these associations in DLB we used pathological and biochemical analysis of the primary visual cortex to identify changes that could underpin RCVH.

Development of passive CLARITY and immunofluorescent labelling of multiple proteins in human cerebellum: understanding mechanisms of neurodegeneration in mitochondrial disease.

CLARITY enables immunofluorescent labelling and imaging of large volumes of tissue to provide a better insight into the three dimensional relationship between cellular morphology and spatial interactions between different cell types. In the current study, we optimise passive CLARITY and immunofluorescent labelling of neurons and mitochondrial proteins in mouse and human brain tissues to gain further insights into mechanisms of neurodegeneration occurring in mitochondrial disease. This is the first study to utilise human cerebellum fixed in paraformaldehyde and cryoprotected in conjunction with formalin-fixed tissues opening up further avenues for use of archived tissue.

Neuronal oscillations: A physiological correlate for targeting mitochondrial dysfunction in neurodegenerative diseases?

Increasingly in the realm of neurological disorders, particularly those involving neurodegeneration, mitochondrial dysfunction is emerging at the core of their pathogenic processes. Most of these diseases still lack effective treatment and are hampered by a shortfall in the development of novel medicines. Clearly new targets that translate well to the clinic are required.

Epilepsy in adults with mitochondrial disease: A cohort study.

Objective: The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease.

Methods: We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7-year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke-like episode, and death.

Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease.

Aims: Cerebellar ataxia is common in patients with mitochondrial disease, and despite previous neuropathological investigations demonstrating vulnerability of the olivocerebellar pathway in patients with mitochondrial disease, the exact neurodegenerative mechanisms are still not clear. We use quantitative quadruple immunofluorescence to enable precise quantification of mitochondrial respiratory chain protein expression in Purkinje cell bodies and their synaptic terminals in the dentate nucleus.

Methods: We investigated NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 protein expression in 12 clinically and genetically defined patients with mitochondrial disease and ataxia and 10 age-matched controls.

Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

Aims: To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for the cardiac management of patients with the most common mitochondrial DNA mutation, m.3243A>G. These studies were initiated after two young, asymptomatic adults harbouring the m.

Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations.

Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter.

Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease.

Aims: Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ-aminobutyric acid (GABA)-ergic interneurones are particularly susceptible to respiratory chain dysfunction.

Quantitative quadruple-label immunofluorescence of mitochondrial and cytoplasmic proteins in single neurons from human midbrain tissue.

Background: Respiratory chain (RC) deficiencies are found in primary mtDNA diseases. Focal RC defects are also associated with ageing and neurodegenerative disorders, e.g.

The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons.

Mitochondrial defects within substantia nigra (SN) neurons are implicated in the pathogenesis of Parkinson's disease. SN neurons show increased mitochondrial defects, mitochondrial DNA deletion levels, and susceptibility to such dysfunction, although the role of mitochondria in neuronal degeneration remains uncertain. In this study, we addressed this important question by exploring changes within the mitochondria of SN neurons from patients with primary mitochondrial diseases to determine whether mitochondrial dysfunction leads directly to neuronal cell loss.

Early-onset cataracts, spastic paraparesis, and ataxia caused by a novel mitochondrial tRNAGlu (MT-TE) gene mutation causing severe complex I deficiency: a clinical, molecular, and neuropathologic study.

Mitochondrial respiratory chain disease is associated with a spectrum of clinical presentations and considerable genetic heterogeneity. Here we report molecular genetic and neuropathologic findings from an adult with an unusual manifestation of mitochondrial DNA disease. Clinical features included early-onset cataracts, ataxia, and progressive paraparesis, with sequencing revealing the presence of a novel de novo m.

Microangiopathy in the cerebellum of patients with mitochondrial DNA disease.

Neuropathological findings in mitochondrial DNA disease vary and are often dependent on the type of mitochondrial DNA defect. Many reports document neuronal cell loss, demyelination, gliosis and necrotic lesions in post-mortem material. However, previous studies highlight vascular abnormalities in patients harbouring mitochondrial DNA defects, particularly in those with the m.

Loss of myelin-associated glycoprotein in kearns-sayre syndrome.

Objective: To explore myelin components and mitochondrial changes within the central nervous system in patients with well-characterized mitochondrial disorders due to nuclear DNA or mitochondrial DNA (mtDNA) mutations.

Design: Immunohistochemical analysis, histochemical analysis, mtDNA sequencing, and real-time and long-range polymerase chain reaction were used to determine the pathogenicity of mtDNA deletions.

Setting: Department of Clinical Pathology, Columbia University Medical Center, and Newcastle Brain Tissue Resource.

Relationship between mitochondria and α-synuclein: a study of single substantia nigra neurons.

Objective: To explore the relationship between α-synuclein pathology and mitochondrial respiratory chain protein levels within single substantia nigra neurons.

Design: We examined α-synuclein and mitochondrial protein expression in substantia nigra neurons of 8 patients with dementia with Lewy bodies, 5 patients with Parkinson disease, and 8 control subjects. Protein expression was determined using immunocytochemistry followed by densometric analysis.