Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% +/- 9.3%; individuals with Parkinson disease, 52.3% +/- 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease.

patients with DoC. The state of consciousness should be classified according to the highest level revealed by any of these three approaches. RESULTS Clinical examinationPICO questions 1-3 refer to clinical signs, PICO questions 4-8 to clinical rating scales. Thirteen

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Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson’s disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies.

Mitochondrial dysfunction plays a major role in the pathogenesis of Parkinson disease (PD). Creatine (Cr) is an ergogenic compound that exerts neuroprotective effects in animal models of PD. We conducted a 2-year placebo-controlled randomized clinical trial on the effect of Cr in 60 patients with PD. Cr improved patient mood and led to a smaller dose increase of dopaminergic therapy but had no effect on overall Unified Parkinson's Disease Rating Scale scores or dopamine transporter SPECT.

We applied the following methods to resting-state EEG data from patients with disorders of consciousness (DOC) for consciousness indexing and outcome prediction: microstates, entropy (i.e. approximate, permutation), power in alpha and delta frequency bands, and connectivity (i.e. weighted symbolic mutual information, symbolic transfer entropy, complex network analysis). Patients with unresponsive wakefulness syndrome (UWS) and patients in a minimally conscious state (MCS) were classified into these two categories by fitting and testing a generalised linear model. We aimed subsequently to develop an automated system for outcome prediction in severe DOC by selecting an optimal subset of features using sequential floating forward selection (SFFS). The two outcome categories were defined as UWS or dead, and MCS or emerged from MCS. Percentage of time spent in microstate D in the alpha frequency band performed best at distinguishing MCS from UWS patients. The average clustering coefficient obtained from thresholding beta coherence performed best at predicting outcome. The optimal subset of features selected with SFFS consisted of the frequency of microstate A in the 2-20 Hz frequency band, path length obtained from thresholding alpha coherence, and average path length obtained from thresholding alpha coherence. Combining these features seemed to afford high prediction power. Python and MATLAB toolboxes for the above calculations are freely available under the GNU public license for non-commercial use ( https://qeeg.wordpress.com ).

Mitochondrial DNA (mtDNA) deletions have been investigated in a number of neurodegenerative diseases. This study aimed to investigate the characteristics of mtDNA deletions found in single substantia nigra neurons from three patient groups: controls, Parkinson disease patients, and a patient with Parkinsonism due to multiple mtDNA deletions. We have identified 89 deletions from these neurons and examined the breakpoint characteristics of them. There was no difference in the types of mtDNA deletions detected in these neurons. These results suggest that the mechanism leading to the formation of these deletions in these three distinct groups could be the same.

Dopaminergic (DA) neuron degeneration is a feature of brain aging but is markedly increased in patients with Parkinson's disease (PD). Recent data indicate elevated metabolic stress as a possible explanation for DA neuron vulnerability. Using laser capture microdissection, we isolated DA neurons from the substantia nigra pars compacta of PD patients, age-matched and young controls to determine transcriptional changes by expression profiling and pathway analysis. We verified our findings by comparison to a published dataset. Parallel processing of isolated neurons and bulk tissue allowed the discrimination of neuronal and glial transcription signals. Our data show that genes known to be involved in neural plasticity, axon and synaptic function, as well as cell fate are differentially regulated in aging DA neurons. The transcription patterns in aging suggest a largely maintained expression of genes in energy-related pathways in surviving neurons, possibly supported by the mediation of PPAR/RAR and CREB signaling. In contrast, a profound down-regulation of genes coding for mitochondrial and ubiquitin--proteasome system proteins was seen in PD when compared to the age-matched controls. This is in accordance with the established mitochondrial dysfunction in PD and provides evidence for mitochondrial impairment at the transcriptional level. In addition, the PD neurons had disrupted pathways that comprise a network involved in the control of energy metabolism and cell survival in response to growth factors, oxidative stress, and nutrient deprivation (PI3K/Akt, mTOR, eIF4/p70S6K and Hif-1α). PI3K/Akt and mTOR signaling are central hubs of this network which is of relevance to longevity and--together with induction of mitochondrial biogenesis--may constitute potential targets for therapeutic intervention.