Isofurans,but not F2-isoprostanes,are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease

F2-isoprostanes (F2-IsoPs) are well-established sensitive and specific markers of oxidative stress in vivo. Isofurans (IsoFs) are also products of lipid peroxidation, but in contrast to F2-IsoPs, their formation is favored when oxygen tension is increased in vitro or in vivo. Mitochondrial dysfunction in Parkinson's disease (PD) may not only lead to oxidative damage to brain tissue but also potentially result in increased intracellular oxygen tension, thereby influencing relative concentrations of F2-IsoPs and IsoFs. In this study, we attempted to compare the levels of F2-IsoPs and IsoFs esterified in phospholipids in the substantia nigra (SN) from patients with PD to those of age-matched controls as well as patients with other neurodegenerative diseases, including dementia with Lewy body disease (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). The results demonstrated that IsoFs but not F2-IsoPs in the SN of patients with PD and DLB were significantly higher than those of controls. Levels of IsoFs and F2-IsoPs in the SN of patients with MSA and AD were indistinguishable from those of age-matched controls. This preferential increase in IsoFs in the SN of patients with PD or DLB not only indicates a unique mode of oxidant injury in these two diseases but also suggests different underlying mechanisms of dopaminergic neurodegeneration in PD and DLB from those of MSA.     

In vitro models of multiple system atrophy from primary cells to induced pluripotent stem cells

Multiple system atrophy (MSA) is a rare neurodegenerative disease with a fatal outcome. Nowadays, only symptomatic treatment is available for MSA patients. The hallmarks of the disease are glial cytoplasmic inclusions (GCIs), proteinaceous aggregates mainly composed of alpha‐synuclein, which accumulate in oligodendrocytes. However, despite the extensive research efforts, little is known about the pathogenesis of MSA. Early myelin dysfunction and alpha‐synuclein deposition are thought to play a major role, but the origin of the aggregates and the causes of misfolding are obscure. One of the reasons for this is the lack of a reliable model of the disease. Recently, the development of induced pluripotent stem cell (iPSC) technology opened up the possibility of elucidating disease mechanisms in neurodegenerative diseases including MSA. Patient specific iPSC can be differentiated in glia and neurons, the cells involved in MSA, providing a useful human disease model. Here, we firstly review the progress made in MSA modelling with primary cell cultures. Subsequently, we focus on the first iPSC‐based model of MSA, which showed that alpha‐synuclein is expressed in oligodendrocyte progenitors, whereas its production decreases in mature oligodendrocytes. We then highlight the opportunities offered by iPSC in studying disease mechanisms and providing innovative models for testing therapeutic strategies, and we discuss the challenges connected with this technique.     

Inorganic mercury in human astrocytes,oligodendrocytes, corticomotoneurons and the locus ceruleus: implications for multiple sclerosis,neurodegenerative disorders and gliomas

Neurotoxic metals have been implicated in the pathogenesis of multiple sclerosis, neurodegenerative disorders and brain tumours but studies of the location of heavy metals in human brains are rare. In a man who injected himself with metallic mercury the cellular location of mercury in his brain was studied after 5 months of continuous exposure to inorganic mercury arising from metallic mercury deposits in his organs. Paraffin sections from the primary motor and sensory cortices and the locus ceruleus in the pons were stained with autometallography to detect inorganic mercury and combined with glial fibrillary acidic protein immunohistochemistry to identify astrocytes. Inorganic mercury was found in grey matter subpial, interlaminar, protoplasmic and varicose astrocytes, white matter fibrous astrocytes, grey but not white matter oligodendrocytes, corticomotoneurons and some locus ceruleus neurons. In summary, inorganic mercury is taken up by five types of human brain astrocytes, as well as by cortical oligodendrocytes, corticomotoneurons and locus ceruleus neurons. Mercury can induce oxidative stress, stimulate autoimmunity and damage DNA, mitochondria and lipid membranes, so its location in these CNS cells suggests it could play a role in the pathogenesis of multiple sclerosis, neurodegenerative conditions such as Alzheimer’s disease and amyotrophic lateral sclerosis, and glial tumours.     

Brain expression level and activity of HDAC6 protein in neurodegenerative dementia

Histone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic protein that plays an especially critical role in the formation of aggresomes, where aggregates of excess protein are deposited. Previous immunohistochemical studies have shown that HDAC6 accumulates in Lewy bodies in Parkinson’s disease and dementia with Lewy bodies (DLB) as well as in glial cytoplasmic inclusions in multiple system atrophy (MSA). However, it is uncertain whether the level and activity of HDAC6 are altered in the brains of patients with neurodegenerative dementia. In the present study, we demonstrated that the level of HDAC6 was not altered in the temporal cortex of patients with Alzheimer’s disease and DLB in comparison with controls. In contrast, the level of HDAC6 was significantly increased in the temporal cortex of patients with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and in the cerebellar white matter of patients with MSA. However, the level of acetylated α-tubulin, one of the substrates of HDAC6, was not altered in FTLD-TDP and MSA relative to controls. These findings suggest that the induced level of HDAC6 in the brain is insufficient for manifestation of its activity in FTLD-TDP and MSA.     

The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease

Accumulation of misfolded proteins as insoluble aggregates occurs in several neurodegenerative diseases. In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), alpha-synuclein (alpha S) accumulates in insoluble inclusions. To identify soluble alpha S oligomers that precede insoluble aggregates, we probed the cytosols of mesencephalic neuronal (MES) cells, normal and alpha S-transgenic mouse brains, and normal, PD, and DLB human brains. All contained highly soluble oligomers of alpha S whose detection was enhanced by delipidation. Exposure of living MES neurons to polyunsaturated fatty acids (PUFAs) increased alpha S oligomer levels, whereas saturated FAs decreased them. PUFAs directly promoted oligomerization of recombinant alphaS. Transgenic mice accumulated soluble oligomers with age. PD and DLB brains had elevated amounts of the soluble, lipid-dependent oligomers. We conclude that alpha S interacts with PUFAs in vivo to promote the formation of highly soluble oligomers that precede the insoluble alpha S aggregates associated with neurodegeneration.     

Is the Vulnerability of Neurons in the Substantia Nigra of Patients with Parkinson's Disease Related to Their Neuromelanin Content?

The contribution of neuromelanin (NM) to the pathogenesis of Parkinson's disease (PD) has long been suspected. In particular, a correlation has been reported between the estimated cell loss in the mesencephalic dopaminergic cell groups and the percentage of NM-pigmented neurons in these cell groups. To test whether the amount of pigment per cell is a critical factor or whether the presence of NM within a neuron is sufficient to account for the degeneration of dopaminergic neurons, the NM content was measured in each neuron from representative sections throughout the ventral mesencephalon of four controls subjects and four patients with PD. Intraneuronal NM was quantified by a densitometric method, using known amounts of synthetic melanin as standards. In control brains, the distribution of melanized neurons in the nigral complex showed a high proportion of lightly melanized neurons in the ventral tegmental area and the pars alpha and gamma of the substantia nigra (SN), whereas heavily melanized neurons were mostly located in the pars beta and lateralis of the SN. An inverse relationship was observed between the percentage of surviving neurons in PD compared with controls and the amount of NM they contain, suggesting that the vulnerability of the dopaminergic neurons is related to their NM content. Factors other than NM may be involved in the differential vulnerability of catecholaminergic neurons in PD. In particular, the constant topography of the cell loss suggests that cell position within the nigral complex is a key factor.     

大鼠脊髓胸段平面少突胶质细胞分布和形态学差异的研究

目的：观察大鼠脊髓胸段（T8-T10）平面中少突胶质细胞在白质和灰质中分布和形态学差异。方法：应用免疫荧光组织化学方法,利用少突胶质细胞特异性标志物一抗大鼠Nogo-A分子单克隆抗体,观察大鼠脊髓胸段平面白质和灰质中少突胶质细胞分布和形态学差异。结果：Nogo—A免疫阳性标记主要集中在少突胶质细胞的胞体、突起及其形成的髓鞘。在冠状切面中,白质中的少突胶质细胞广泛分布,而灰质中少突胶质细胞主要分布于神经元的周围;白质中少突胶质细胞胞体较灰质中少突胶质细胞的胞体大,且白质中少突胶质细胞突起及形成的髓鞘结构较灰质中明显。在矢状切面中,白质中少突胶质细胞多成”串珠状”排列,而灰质中少突胶质细胞则紧贴神经元。在脊髓近端背根结结构中,可以观察到少突胶质细胞形成的轴突呈”蜂窝状”结构。结论：应用抗大鼠Nogo—A分子单克隆抗体的免疫荧光组织化学染色方法能够较好展示少突胶质细胞分布特点和形态学差异,与少突胶质细胞类别（束内细胞,卫星细胞）和功能特点相适应,为进一步研究生理和病理条件下,少突胶质细胞的机能奠定基础。     

Neuroanatomical Correlates of Theory of Mind Deficit in Parkinson’s Disease: A Multimodal Imaging Study

BackgroundParkinson’s disease (PD) patients show theory of mind (ToM) deficit since the early stages of the disease, and this deficit has been associated with working memory, executive functions and quality of life impairment. To date, neuroanatomical correlates of ToM have not been assessed with magnetic resonance imaging in PD. The main objective of this study was to assess cerebral correlates of ToM deficit in PD. The second objective was to explore the relationships between ToM, working memory and executive functions, and to analyse the neural correlates of ToM, controlling for both working memory and executive functions.MethodsThirty-seven PD patients (Hoehn and Yahr median = 2.0) and 15 healthy controls underwent a neuropsychological assessment and magnetic resonance images in a 3T-scanner were acquired. T1-weighted images were analysed with voxel-based morphometry, and white matter integrity and diffusivity measures were obtained from diffusion weighted images and analysed using tract-based spatial statistics.ResultsPD patients showed impairments in ToM, working memory and executive functions; grey matter loss and white matter reduction compared to healthy controls. Grey matter volume decrease in the precentral and postcentral gyrus, middle and inferior frontal gyrus correlated with ToM deficit in PD. White matter in the superior longitudinal fasciculus (adjacent to the parietal lobe) and white matter adjacent to the frontal lobe correlated with ToM impairment in PD. After controlling for executive functions, the relationship between ToM deficit and white matter remained significant for white matter areas adjacent to the precuneus and the parietal lobe.ConclusionsFindings reinforce the existence of ToM impairment from the early Hoehn and Yahr stages in PD, and the findings suggest associations with white matter and grey matter volume decrease. This study contributes to better understand ToM deficit and its neural correlates in PD, which is a basic skill for development of healthy social relationships.     

Diffusion Tensor Imaging of Parkinson’s Disease,Multiple System Atrophy and Progressive Supranuclear Palsy: A Tract-Based Spatial Statistics Study

Although often clinically indistinguishable in the early stages, Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) have distinct neuropathological changes. The aim of the current study was to identify white matter tract neurodegeneration characteristic of each of the three syndromes. Tract-based spatial statistics (TBSS) was used to perform a whole-brain automated analysis of diffusion tensor imaging (DTI) data to compare differences in fractional anisotropy (FA) and mean diffusivity (MD) between the three clinical groups and healthy control subjects. Further analyses were conducted to assess the relationship between these putative indices of white matter microstructure and clinical measures of disease severity and symptoms. In PSP, relative to controls, changes in DTI indices consistent with white matter tract degeneration were identified in the corpus callosum, corona radiata, corticospinal tract, superior longitudinal fasciculus, anterior thalamic radiation, superior cerebellar peduncle, medial lemniscus, retrolenticular and anterior limb of the internal capsule, cerebral peduncle and external capsule bilaterally, as well as the left posterior limb of the internal capsule and the right posterior thalamic radiation. MSA patients also displayed differences in the body of the corpus callosum corticospinal tract, cerebellar peduncle, medial lemniscus, anterior and superior corona radiata, posterior limb of the internal capsule external capsule and cerebral peduncle bilaterally, as well as the left anterior limb of the internal capsule and the left anterior thalamic radiation. No significant white matter abnormalities were observed in the PD group. Across groups, MD correlated positively with disease severity in all major white matter tracts. These results show widespread changes in white matter tracts in both PSP and MSA patients, even at a mid-point in the disease process, which are not found in patients with PD.     

Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathies

Alpha-synuclein (alphaS) is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson's disease (PD) and the related disorder, dementia with Lewy bodies (DLB). A central question about the role of alphaS in the pathogenesis of PD and DLB concerns how this normally soluble protein assembles into insoluble aggregates associated with neuronal dysfunction. We recently detected highly soluble oligomers of alphaS in normal brain supernatants and observed their augmentation in PD and DLB brains. Further, we found that polyunsaturated fatty acids (PUFAs) enhanced alphaS oligomerization in intact mesencephalic neuronal cells. We now report the presence of elevated PUFA levels in PD and DLB brain soluble fractions. Higher PUFA levels were also detected in the supernatants and high-speed membrane fractions of neuronal cells over-expressing wild-type or PD-causing mutant alphaS. This increased PUFA content in the membrane fraction was accompanied by increased membrane fluidity in the alphaS overexpressing neurons. In accord, membrane fluidity and the levels of certain PUFAs were decreased in the brains of mice genetically deleted of alphaS. Together with our earlier observations, these results suggest that alphaS-PUFA interactions help regulate neuronal PUFA levels as well as the oligomerization state of alphaS, both normally and in human synucleinopathies.     

Neuropathology in mice expressing mouse alpha-synuclein

α-Synuclein (αSN) in human is tightly linked both neuropathologically and genetically to Parkinson's disease (PD) and related disorders. Disease-causing properties in vivo of the wildtype mouse ortholog (mαSN), which carries a threonine at position 53 like the A53T human mutant version that is genetically linked to PD, were never reported. To this end we generated mouse lines that express mαSN in central neurons at levels reaching up to six-fold compared to endogenous mαSN. Unlike transgenic mice expressing human wildtype or mutant forms of αSN, these mαSN transgenic mice showed pronounced ubiquitin immunopathology in spinal cord and brainstem. Isoelectric separation of mαSN species revealed multiple isoforms including two Ser129-phosphorylated species in the most severely affected brain regions. Neuronal Ser129-phosphorylated αSN occurred in granular and small fibrillar aggregates and pathological staining patterns in neurites occasionally revealed a striking ladder of small alternating segments staining either for Ser129-phosphorylated αSN or ubiquitin but not both. Axonal degeneration in long white matter tracts of the spinal cord, with breakdown of myelin sheaths and degeneration of neuromuscular junctions with loss of integrity of the presynaptic neurofilament network in mαSN transgenic mice, was similar to what we have reported for mice expressing human αSN wildtype or mutant forms. In hippocampal neurons, the mαSN protein accumulated and was phosphorylated but these neurons showed no ubiquitin immunopathology. In contrast to the early-onset motor abnormalities and muscle weakness observed in mice expressing human αSN, mαSN transgenic mice displayed only end-stage phenotypic alterations that manifested alongside with neuropathology. Altogether these findings show that increased levels of wildtype mαSN does not induce early-onset behavior changes, but drives end-stage pathophysiological changes in murine neurons that are strikingly similar to those evoked by expression of human wildtype or mutant forms.     

Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications

Multiple system atrophy (MSA) is a fatal rapidly progressive α-synucleinopathy, characterized by α-synuclein accumulation in oligodendrocytes. It is accepted that the pathological α-synuclein accumulation in the brain of MSA patients plays a leading role in the disease process, but little is known about the events in the early stages of the disease. In this study we aimed to define potential roles of the miRNA-mRNA regulatory network in the early pre-motor stages of the disease, i.e., downstream of α-synuclein accumulation in oligodendroglia, as assessed in a transgenic mouse model of MSA. We investigated the expression patterns of miRNAs and their mRNA targets in substantia nigra (SN) and striatum, two brain regions that undergo neurodegeneration at a later stage in the MSA model, by microarray and RNA-seq analysis, respectively. Analysis was performed at a time point when α-synuclein accumulation was already present in oligodendrocytes at neuropathological examination, but no neuronal loss nor deficits of motor function had yet occurred. Our data provide a first evidence for the leading role of gene dysregulation associated with deficits in immune and inflammatory responses in the very early, non-symptomatic disease stages of MSA. While dysfunctional homeostasis and oxidative stress were prominent in SN in the early stages of MSA, in striatum differential gene expression in the non-symptomatic phase was linked to oligodendroglial dysfunction, disturbed protein handling, lipid metabolism, transmembrane transport and altered cell death control, respectively. A large number of putative miRNA-mRNAs interaction partners were identified in relation to the control of these processes in the MSA model. Our results support the role of early changes in the miRNA-mRNA regulatory network in the pathogenesis of MSA preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of MSA.     

Study of Cu chemical state inside single neurons from Parkinson's disease and control substantia nigra using the micro-XANES technique

Parkinson's disease (PD) is referred to as idiopathic disorder, which means that its causes have not been found yet. However, a few processes such as oxidative stress, protein aggregation and mitochondrial dysfunction are suspected to lead to the atrophy and death of substantia nigra (SN) neurons in case of this neurodegenerative disorder. Cu is a trace element whose role in the pathogenesis of PD is widely discussed. The investigation of Cu oxidation state inside single nerve cells from SN of PD and control cases may shed some new light on the role of this element in PD. The differences in Cu chemical state were investigated with the use of X-ray absorption near edge structure (XANES) spectroscopy. The least-square fitting method was applied for the analysis of XANES spectra. The comparison of the positions of white line, multiple scattering and pre-edge peak maximum at the energy scale did not reveal the existence of differences in Cu chemical state between PD and control samples. However, it was found that most of the Cu inside SN neurons occurs in tetrahedral environment and probably as Cu(II).     

Do mtDNA Mutations Participate in the Pathogenesis of Sporadic Parkinson’s Disease?

The pathogenesis of sporadic Parkinson’s disease (PD) remains enigmatic. Mitochondrial complex-I defects are known to occur in the substantia nigra (SN) of PD patients and are also debated in some extracerebral tissues. Early sequencing efforts of the mitochondrial DNA (mtDNA) did not reveal specific mutations, but a long lasting discussion was devoted to the issue of randomly distributed low level point mutations, caused by oxidative stress. However, a potential functional impact remained a matter of speculation, since heteroplasmy (mutational load) at any base position analyzed, remained far below the relevant functional threshold. A clearly age-dependent increase of the ‘common mtDNA deletion’ had been demonstrated in most brain regions by several authors since 1992. However, heteroplasmy did hardly exceed 1% of total mtDNA. It became necessary to exploit PCR techniques, which were able to detect any deletion in a few microdissected dopaminergic neurons of the SN. In 2006, two groups published biochemically relevant loads of somatic mtDNA deletions in these neurons. They seem to accumulate to relevant levels in the SN dopaminergic neurons of aged individuals in general, but faster in those developing PD. It is reasonable to assume that this accumulation causes mitochondrial dysfunction of the SN, although it cannot be taken as a final proof for an early pathogenetic role of this dysfunction. Recent studies demonstrate a distribution of deletion breakpoints, which does not differ between PD, aging and classical mitochondrial disorders, suggesting a common, but yet unknown mechanism.     

多巴胺代谢异常在帕金森病相关病理变化中的作用

帕金森病(Parkinson's disease,PD)是常见的中枢神经系统退行性疾病之一,其主要病理学特征是中脑黑质部的多巴胺(dopamine,DA)能神经元选择性丢失.虽然已发现基因易感性、衰老、环境毒素等因素与PD发病有关,但导致DA能神经元退行性死亡的细胞分子机制仍不明确.DA代谢是DA能神经元中的重要生理过...     

Screening of Toll-Like Receptors Expression in Multiple System Atrophy Brains

The family of Toll-like receptors (TLRs) plays a key role in controlling innate immune responses to a wide variety of pathogen-associated molecules. It was recently suggested that TLRs have an important role in the crosstalk between neurons and glial cells in the central nervous system, thus their deregulation may play a role in neurodegeneration. Multiple system atrophy (MSA) together with Parkinson’s disease belongs to a diverse group of neurodegenerative conditions termed α-synucleinopathies. MSA is a fatal late onset disease characterized by the presence of α-synuclein positive glial cytoplasmic inclusions in oligodendrocytes. α-Synuclein can act as a danger-associated molecular pattern and alter TLR expression thereby activating inflammatory responses in the brain. In this study, using real-time PCR, we assessed the expression of TLRs (TLR1-10) in selected areas of MSA brains (substantia nigra, striatum, cerebral cortex, and nucleus dentatus) in comparison with normal controls. We show evidence for increased levels of mRNA-encoding hTLR-3, hTLR-4, and hTLR-5 in substantia nigra, striatum, cerebral cortex, and nucleus dentatus from MSA brains versus normal controls. The levels of expression of hTLR-1 mRNA were elevated in substantia nigra and striatum whereas levels of hTLR-8 and hTLR-9 mRNAs were significantly higher in cerebella from MSA patients. The concerted alteration of expression of multiple TLRs in MSA brains can be of relevance for understanding the pathogenesis of the disease.     

Serum Uric Acid and Nigral Iron Deposition in Parkinson’s Disease: A Pilot Study

Background

Uric acid (UA) is an endogenous antioxidant which is known to reduce oxidative stress and also chelate iron ion. Recent studies have provided evidence that UA may play a neuroprotective role in Parkinson’s disease (PD). However, it is unknown whether UA relates to nigral iron deposition, which is a characteristic pathophysiological alteration in PD. The aim of this study was to determine the potential relationship of these two markers in patients with PD.

Methods

A total of 30 patients of PD and 25 age- and gender- matched healthy controls underwent 3-Tesla MRI and laboratory tests including serum UA levels. We assessed iron levels by measuring phase shift values using susceptibility-weighted image. Mean phase shift values of the substantia nigra (SN), red nucleus, head of the caudate nucleus, globus pallidus, putamen, thalamus, and frontal white matter were calculated and correlated with serum UA levels.

Results

Serum UA levels were significantly decreased in the PD patients than in the controls. Phase shift values in bilateral SN were significantly increased in the PD patients than in the controls. There was no significant correlation between serum UA levels and nigral phase shift values.

Conclusions

As previous studies, low serum UA level and increased nigral iron content in the PD was reconfirmed in this study. However, we failed to find the relationship between these two markers. Our data suggest that serum UA may not be important determinant of nigral iron deposition in PD.     

Meta-analysis of iron metabolism markers levels of Parkinson’s disease patients determined by fluid and MRI measurements

BackgroundParkinson’ s disease (PD) is a progressive neurodegenerative disease featured neuropathologically by the loss of dopaminergic neurons of the substantia nigra (SN). Iron overload in the SN is mainly relative to the pathology and pathogenesis of PD. Postmortem samples of PD has indicated the increased levels of brain iron. However, there is no consensus on iron content through iron-sensitive magnetic resonance imaging (MRI) techniques and the alteration of iron and iron related metabolism markers levels in blood and cerebrospinal fluids (CSF) are still unclear based on the current studies. In this study, we performed a meta-analysis to explore the iron concentration and iron metabolism markers levels through iron-sensitive MRI quantification and body fluid.MethodsA comprehensive literature search was performed in PubMed, EMBASE and Cochrane Library databases for relevant published studies that analyzed iron load in the SN of PD patients using quantitative susceptibility mapping (QSM) or susceptibility weighting imaging (SWI), and iron metabolism markers, iron, ferritin, transferrin, total iron-binding capacity（TIBC）in CSF sample or serum/plasma sample (from Jan 2010 to Sep 2022 to filter these inaccurate researches attributed to unadvanced equipment, inaccurate analytical methods). Standardized mean differences (SMD) or mean differences (MD) and 95% confidence intervals (CI) with random or fixed effect model was used to estimate the results.ResultsForty-two articles fulfilled the inclusion criteria including 19 for QSM, 6 for SWI, and 17 for serum/plasma/CSF sample including 2874 PD patients and 2821 healthy controls (HCs). Our meta-analysis results founded a notable difference for QSM values increase (19.67, 95% CI=18.69–20.64) and for SWI measurements (−1.99, 95% CI= −3.52 to −0.46) in the SN in PD patients. However, the serum/plasma/CSF iron levels and serum/plasma ferritin, transferrin, total iron-binding capacity (TIBC) did not differ significantly between PD patients and HCs.ConclusionsOur meta-analysis showed the consistent increase in the SN in PD patients using QSM and SWI techniques of iron-sensitive MRI measures while no significant differences were observed in other iron metabolism markers levels.     

Decreased NAA in Gray Matter is Correlated with Decreased Availability of Acetate in White Matter in Postmortem Multiple Sclerosis Cortex

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) which leads to progressive neurological disability. Our previous studies have demonstrated mitochondrial involvement in MS cortical pathology and others have documented decreased levels of the neuronal mitochondrial metabolite N-acetyl aspartate (NAA) in the MS brain. While NAA is synthesized in neurons, it is broken down in oligodendrocytes into aspartate and acetate. The resulting acetate is incorporated into myelin lipids, linking neuronal mitochondrial function to oligodendrocyte-mediated elaboration of myelin lipids in the CNS. In the present study we show that treating human SH-SY5Y neuroblastoma cells with the electron transport chain inhibitor antimycin A decreased levels of NAA as measured by HPLC. To better understand the significance of the relationship between mitochondrial function and levels of NAA and its breakdown product acetate on MS pathology we then quantitated the levels of NAA and acetate in MS and control postmortem tissue blocks. Regardless of lesion status, we observed that levels of NAA were decreased 25 and 32 % in gray matter from parietal and motor cortex in MS, respectively, compared to controls. Acetate levels in adjacent white matter mirrored these decreases as evidenced by the 36 and 45 % reduction in acetate obtained from parietal and motor cortices. These data suggest a novel mechanism whereby mitochondrial dysfunction and reduced NAA levels in neurons may result in compromised myelination by oligodendrocytes due to decreased availability of acetate necessary for the synthesis of myelin lipids.     

Proteomic analysis of human substantia nigra identifies novel candidates involved in Parkinson's disease pathogenesis

Parkinson's disease (PD) pathology spreads throughout the brain following a region‐specific process predominantly affecting the substantia nigra (SN) pars compacta. SN exhibits a progressive loss of dopaminergic neurons responsible for the major cardinal motor symptoms, along with the occurrence of Lewy bodies in the surviving neurons. To gain new insights into the underlying pathogenic mechanisms in PD, we studied postmortem nigral tissues dissected from pathologically confirmed PD cases (n = 5) and neurologically intact controls (n = 8). Using a high‐throughput shotgun proteomic strategy, we simultaneously identified 1795 proteins with concomitant quantitative data. To date, this represents the most extensive catalog of nigral proteins. Of them, 204 proteins displayed significant expression level changes in PD patients versus controls. These were involved in novel or known pathogenic processes including mitochondrial dysfunction, oxidative stress, or cytoskeleton impairment. We further characterized four candidates that might be relevant to PD pathogenesis. We confirmed the differential expression of ferritin‐L and seipin by Western blot and demonstrated the neuronal localization of gamma glutamyl hydrolase and nebulette by immunohistochemistry. Our preliminary findings suggest a role for nebulette overexpression in PD neurodegeneration, through mechanisms that may involve cytoskeleton dynamics disruption. All MS data have been deposited in the ProteomeXchange with identifier PXD000427 ( http://proteomecentral.proteomexchange.org/dataset/PXD000427 ).