Oligodendroglial Cytoplasmic Inclusions Research Articles

Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials.

Multiple system atrophy is a rare, debilitating, adult-onset neurodegenerative disorder that manifests clinically as a diverse combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is pathologically characterized by oligodendroglial cytoplasmic inclusions containing abnormally aggregated α-synuclein. According to the updated Movement Disorder Society diagnostic criteria for multiple system atrophy, the diagnosis of clinically established multiple system atrophy requires the manifestation of autonomic dysfunction in combination with poorly levo-dopa responsive parkinsonism and/or cerebellar syndrome. Although symptomatic management of multiple system atrophy can substantially improve quality of life, therapeutic benefits are often limited, ephemeral, and they fail to modify the disease progression and eradicate underlying causes. Consequently, effective breakthrough treatments that target the causes of disease are needed. Numerous preclinical and clinical studies are currently focusing on a set of hallmarks of neurodegenerative diseases to slow or halt the progression of multiple system atrophy: pathological protein aggregation, synaptic dysfunction, aberrant proteostasis, neuronal inflammation, and neuronal cell death. Meanwhile, specific biomarkers and measurements with higher specificity and sensitivity are being developed for the diagnosis of multiple system atrophy, particularly for early detection of the disease. More intriguingly, a growing number of new disease-modifying candidates, which can be used to design multi-targeted, personalized treatment in patients, are being investigated, notwithstanding the failure of most previous attempts.

Sobetirome rescues α-synuclein-mediated demyelination in an in vitro model of multiple system atrophy.

Multiple system atrophy (MSA) is a rare and rapidly progressive atypical parkinsonian disorder characterized by oligodendroglial cytoplasmic inclusions containing α-synuclein (α-syn), demyelination, inflammation and neuronal loss. To date, no disease-modifying therapy is available. Targeting α-syn-driven oligodendroglial dysfunction and demyelination presents a potential therapeutic approach for restricting axonal dysfunction, neuronal loss and disease progression. The present study investigated the promyelinogenic potential of sobetirome, a blood-brain barrier permeable and central nervous system selective thyromimetic in the context of an in vitro MSA model. Oligodendrocyte precursor cells (OPCs) were obtained from transgenic mice overexpressing human α-syn specifically in oligodendrocytes (MBP29 mouse line), a well-described MSA model, and non-transgenic littermates. mRNA and protein expression analyses revealed a substantial rescue effect of sobetirome on myelin-specific proteins in control and α-syn overexpressing oligodendrocytes. Furthermore, myelination analysis using nanofibres confirmed that sobetirome increases both the length and number of myelinated segments per oligodendrocyte in primary murine α-syn overexpressing oligodendrocytes and their respective control. These results suggest that sobetirome may be a promising thyromimetic compound targeting an important neuropathological hallmark of MSA.

α-Synuclein pathology in post-mortem retina and optic nerve is specific for α-synucleinopathies

There is increasing interest in studying retinal biomarkers for various neurodegenerative diseases. Specific protein aggregates associated with neurodegenerative diseases are present in the retina and could be visualised in a non-invasive way. This study aims to assess the specificity and sensitivity of retinal α-synuclein aggregates in neuropathologically characterised α-synucleinopathies, other neurodegenerative diseases and non-neurological controls. Post-mortem eyes (N = 99) were collected prospectively through the Netherlands Brain Bank from donors with Parkinson’s disease (and dementia), dementia with Lewy bodies, multiple system atrophy, Alzheimer’s disease, other neurodegenerative diseases and non-neurological controls. Multiple retinal and optic nerve cross-sections were immunostained with anti-α-synuclein antibodies (LB509, KM51, and anti-pSer129) and assessed for aggregates and inclusions. α-Synuclein was observed as Lewy neurites in the retina and oligodendroglial cytoplasmic inclusions in the optic nerve and was highly associated with Lewy body disease (P < 0.001) and multiple system atrophy (P = 0.001). In all multiple system atrophy cases, the optic nerve showed oligodendroglial cytoplasmic inclusions, while retinal Lewy neurites were absent, despite coincidental brain Lewy pathology. With high specificity (97%) and sensitivity (82%), retinal/optic nerve α-synuclein differentiates primary α-synucleinopathies from other cases and controls. α-Synuclein pathology occurs specifically in the retina and optic nerve of primary α-synucleinopathies as opposed to other neurodegenerative diseases—with and without α-synuclein co-pathology—and controls. The absence of retinal Lewy neurites in multiple system atrophy could contribute to the development of an in vivo retinal biomarker that discriminates between Lewy body disease and multiple system atrophy.

A pathologically confirmed case of combined amyotrophic lateral sclerosis with C9orf72 mutation and multiple system atrophy

Hexanucleotide repeat expansions in C9orf72 account for a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. There have been occasional reported cases associated with this expansion but also additional extrapyramidal clinical features. However, only very rarely has there been pathological confirmation of a parkinsonian syndrome associated with a C9orf72 repeat expansion. To date, as far as we are aware, there have been no reported pathologically confirmed cases of ALS with C9orf72 mutation and multiple system atrophy (MSA). We report a case of a man who initially presented with extrapyramidal features, including cogwheel rigidity, and, therefore, was clinically considered likely to have Parkinson's disease or a parkinsonian syndrome. Subsequent examination six months later revealed additional abnormal upper and lower motor neuron signs, raising the strong possibility of ALS. He had a rapid clinical decline and died 16 months after the first presentation. It was noted that his father also had ALS, and that his mother had a parkinsonian syndrome, suggestive of progressive supranuclear palsy. The macroscopic and microscopic examination of the brain and spinal cord revealed ALS pathology with neuronal loss, especially of the anterior horns of the cord and the motor cortex. This was associated with numerous neuronal cytoplasmic inclusions immunoreactive for phosphorylated transactivation response DNA‐binding protein of 43 Da (TDP43). There were additional pathological features, including p62‐immunoreactive cerebellar neuronal cytoplasmic inclusions, fully in keeping with a C9orf72 repeat expansion, and this was confirmed on molecular analysis. However, there was also α‐synuclein pathology in the form of oligodendroglial cytoplasmic inclusions in the basal ganglia, cerebellum, and brainstem, indicative of MSA. To our knowledge, this is the first reported case of pathologically confirmed combined ALS‐C9orf72 and MSA.

Brain TDP-43 pathology in corticobasal degeneration: Topographical correlation with neuronal loss.

Neuronal and glial inclusions comprising transactive response DNA-binding protein of 43 kDa (TDP-43) have been identified in the brains of patients with corticobasal degeneration (CBD), and a possible correlation between the presence of these inclusions and clinical phenotypes has been speculated. However, the significance of TDP-43 pathology in the pathomechanism of CBD has remained unclear. Here, we investigated the topographical relationship between TDP-43 inclusions and neuronal loss in CBD. We estimated semi-quantitatively neuronal loss and TDP-43 pathology in the form of neuronal cytoplasmic inclusions (NCIs), astrocytic inclusions (AIs), oligodendroglial cytoplasmic inclusions (GCIs), and dystrophic neurites in 22 CNS regions in 10 patients with CBD. Then, the degree of correlation between the severity of neuronal loss and the quantity of each type of TDP-43 inclusion was assessed. We also investigated tau pathology in a similar manner. TDP-43 pathology was evident in nine patients. The putamen and globus pallidus were the regions most frequently affected (80%). NCIs were the most prominent form, and their quantity was significantly correlated with the severity of neuronal loss in more than half of the regions examined. The quantities of TDP-43 NCIs and tau NCIs were correlated in only a few regions. The number of regions where the quantities of TDP-43 AIs and GCIs were correlated with the severity of neuronal loss was apparently small in comparison with that of NCIs. TDP-43 alterations in neurons, not closely associated with tau pathology, may be involved in the pathomechanism underlying neuronal loss in CBD. There was a significant topographical correlation between neuronal cytoplasmic aggregation of TDP-43 and neuronal loss in CBD, suggesting that TDP-43 protein aberration might be associated with neuronal degeneration in CBD. There was no close correlation between the burden of TDP-43 and that of tau in neurons.

Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy

Multiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.

Contribution of the astrocytic tau pathology to synapse loss in progressive supranuclear palsy and corticobasal degeneration.

Primary 4‐repeat tauopathies with frontotemporal lobar degeneration (FTLD) like Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration (CBD) show diverse cellular pathology in various brain regions. Besides shared characteristics of neuronal and oligodendroglial cytoplasmic inclusions of accumulated hyperphosphorylated tau protein (pTau), astrocytes in PSP and CBD contain pathognomonic pTau aggregates — hence, lending the designation tufted astrocytes (TA) or astrocytic plaques (AP), respectively. pTau toxicity is most commonly assigned to neurons, whereas the implications of astrocytic pTau for maintaining neurotransmission within the tripartite synapse of human brains is not well understood. We performed immunofluorescent synapse labeling and automated puncta quantification in the medial frontal gyrus (MFG) and striatal regions from PSP and CBD postmortem samples to capture morphometric synaptic alterations. This approach indicated general synaptic losses of both, excitatory and inhibitory bipartite synapses in the frontal cortex of PSP cases, whereas in CBD lower synapse densities were only related to astrocytic plaques. In contrast to tufted astrocytes in PSP, affected astrocytes in CBD could not preserve synaptic integrity within their spatial domains, when compared to non‐affected internal astrocytes or astrocytes in healthy controls. These findings suggest a pTau pathology‐associated role of astrocytes in maintaining connections within neuronal circuits, considered as the microscopic substrate of cognitive dysfunction in CBD. By contrasting astrocytic‐synaptic associations in both diseases, we hereby highlight astrocytic pTau as an important subject of prospective research and as a potential cellular target for therapeutic approaches in the primary tauopathies PSP and CBD.

Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy.

Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6–9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available. Consequently, distinct pharmacological targets have been explored and investigated in clinical studies based on MSA-related symptoms and pathomechanisms. Parkinsonism, cerebellar ataxia, and autonomic failure are the most important symptoms targeted by symptomatic treatments in current clinical trials. The most prominent pathological hallmark is oligodendroglial cytoplasmic inclusions containing alpha-synuclein, thus classifying MSA as synucleinopathy. Additionally, myelin and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting α-syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy.

Neuropathology of autonomic dysfunction in synucleinopathies.

The synucleinopathies-Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure-result from distinct patterns of abnormal α-synuclein aggregation throughout the nervous system. Autonomic dysfunction in these disorders results from variable involvement of the central and peripheral autonomic networks. The major pathologic hallmark of Parkinson's disease and dementia with Lewy bodies is Lewy bodies and Lewy neurites; of multiple system atrophy, oligodendroglial cytoplasmic inclusions; and of pure autonomic failure, peripheral neuronal cytoplasmic inclusions. Clinical manifestations include orthostatic hypotension, thermoregulatory dysfunction, gastrointestinal dysmotility, and urogenital dysfunction with neurogenic bladder and sexual dysfunction. Strong evidence supports isolated idiopathic rapid eye movement sleep disorder as a significant risk factor for the eventual development of synucleinopathies with autonomic and/or motor involvement. In contrast, some neurologically normal elderly individuals have Lewy-related pathology. Future work may reveal protective or vulnerability factors that allow some patients to harbor Lewy pathology without overt autonomic dysfunction. © 2018 International Parkinson and Movement Disorder Society.

Progressive striatonigral degeneration\xa0in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.

Perry Syndrome: A Distinctive Type of TDP-43 Proteinopathy

Perry syndrome is a rare atypical parkinsonism with depression, apathy, weight loss, and central hypoventilation caused by mutations in dynactin p150glued (DCTN1). A rare distal hereditary motor neuropathy, HMN7B, also has mutations in DCTN1. Perry syndrome has TAR DNA-binding protein of 43 kDa (TDP-43) inclusions as a defining feature. Other TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with and without motor neuron disease (FTLD-MND). TDP-43 forms aggregates in neuronal cytoplasmic inclusions (NCIs), neuronal intranuclear inclusions, dystrophic neurites (DNs), as well as axonal spheroids, oligodendroglial cytoplasmic inclusions, and perivascular astrocytic inclusions (PVIs). We performed semiquantitative assessment of these lesions and presence of dynactin subunit p50 lesions in 3 cases of Perry syndrome and one of HMN7B. We compared them with 3 cases of FTLD-MND, 3 of ALS, and 3 of hippocampal sclerosis (HpScl). Perry syndrome had NCIs, DNs, and frequent PVIs and spheroids. Perry syndrome cases were similar, but different from ALS, FTLD-MND, and HpScl. TDP-43 pathology was not detected in HMN7B. Dynactin p50 inclusions were observed in both Perry syndrome and HMN7B, but not in the other conditions. These results suggest that Perry syndrome may be distinctive type of TDP-43 proteinopathy.

Overexpression of α-synuclein in oligodendrocytes does not increase susceptibility to focal striatal excitotoxicity.

BackgroundMultiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease characterized by α-synuclein (α-syn) positive oligodendroglial cytoplasmic inclusions. The latter are associated with a neuronal multisystem neurodegeneration targeting central autonomic, olivopontocerebellar and striatonigral pathways, however the underlying mechanisms of neuronal cell death are poorly understood. Previous experiments have shown that oligodendroglial α-syn pathology increases the susceptibility to mitochondrial stress and proteasomal dysfunction leading to enhanced MSA-like neurodegeneration. Here we analyzed whether oligodendroglial α-syn overexpression in a transgenic mouse model of MSA synergistically interacts with focal neuronal excitotoxic damage generated by a striatal injection of quinolinic acid (QA) to affect the degree of striatal neuronal loss.ResultsQA injury led to comparable striatal neuronal loss and optical density of astro- and microgliosis in the striatum of transgenic and control mice. Respectively, no differences were identified in drug-induced rotation behavior or open field behavior between the groups.ConclusionsThe failure of oligodendroglial α-syn pathology to exacerbate striatal neuronal loss resulting from QA excitotoxicity contrasts with enhanced striatal neurodegeneration due to oxidative or proteolytic stress, suggesting that enhanced vulnerability to excitotoxicity does not occur in oligodendroglial α-synucleinopathy like MSA.

Neuroinflammation in Multiple System Atrophy: Response to and Cause of α-Synuclein Aggregation.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease presenting with combinations of autonomic dysfunction, parkinsonism, cerebellar ataxia and/or pyramidal signs. Oligodendroglial cytoplasmic inclusions (GCIs) rich in α-synuclein (α-syn) constitute the disease hallmark, accompanied by neuronal loss and activation of glial cells which indicate neuroinflammation. Recent studies demonstrate that α-syn may be released from degenerating neurons to mediate formation of abnormal inclusion bodies and to induce neuroinflammation which, interestingly, might also favor the formation of intracellular α-syn aggregates as a consequence of cytokine release and the shift to a pro-inflammatory environment. Here, we critically review the relationships between α-syn and astrocytic and microglial activation in MSA to explore the potential of therapeutics which target neuroinflammation.

Region-Specific Alterations of Matrix Metalloproteinase Activity in Multiple System Atrophy.

MSA is a sporadic progressive neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. The pathological hallmark of MSA is the accumulation of alpha-synuclein aggregates in the cytoplasm of oligodendrocytes along with neuronal loss and neuroinflammation, as well as blood-brain barrier dysfunction and myelin deterioration. Matrix metalloproteinases are zinc-dependent endopeptidases involved in the remodeling of the extracellular matrix, demyelination, and blood-brain barrier permeability. Several lines of evidence indicate a role for these enzymes in various pathological processes, including stroke, multiple sclerosis, Parkinson's, and Alzheimer's disease. This study aimed to assess potential alterations of matrix metalloproteinase-1, -2, -3, and -9 expression or activity in MSA postmortem brain tissue. Gelatin zymography revealed increased matrix metalloproteinase-2 activity in the putamen, but not in the frontal cortex, of MSA patients relative to controls. Immunohistochemistry revealed increased number of glial cells positive for matrix metalloproteinase-1, -2, and -3 in the putamen and frontal cortex of MSA patients. Double immunofluorescence revealed that matrix metalloproteinase-2 and -3 were expressed in astrocytes and microglia. Only matrix metalloproteinase-2 colocalized with alpha-synuclein in oligodendroglial cytoplasmic inclusions. These results demonstrate widespread alterations of matrix metalloproteinase expression in MSA and a pattern of increased matrix metalloproteinase-2 expression and activity affecting preferentially a brain region severely affected (putamen) over a relatively spared region (frontal cortex). Elevated matrix metalloproteinase expression may thus contribute to the disease process in MSA by promoting blood-brain barrier dysfunction and/or myelin degradation.

[Histopathological and immunohistochemical study of spinal cord tissues in neurodegenerative diseases].

To investigate histopathology and proteinopathy in the spinal cord of patients with common neurodegenerative diseases. Spinal cord tissues from clinically and neuropathologically confirmed neruodegnerative diseases were enrolled in this study, including 3 cases of multiple system strophy, 4 cases of amyotrophic lateral sclerosis, 5 cases of Alzheimer's disease (AD, included 2 cases of AD combined with Parkinson's disease), 2 cases of progressive supranuclear palsy, 1 case of dementia with lewy body and 1 case of corticobasal degeneration from 1955 to 2013 at Chinese People's Liberation Army General Hospital. Four normal control cases were also included. Routine HE and Gallyas-Braak staining, and immunohistochemical stainings for anti-PHF tau (AT8), anti-α-synuclein, anti-TDP-43 and anti-ubiquitin were performed. Examination of the spinal cord in 3 cases with multiple system strophy revealed severe neuron loss in the intermediolateral nucleus of thoracic segment and Onuf's nucleus of the sacral segment, along with moderate neuron loss in the anterior horn of the cervical segment and mild myelin pallor in the anterior funiculus and anterolateral funiculus in the cervical and thoracic segments. Large amount of argentophilic, ubiquitin and synuclein positive oligodendroglial cytoplasmic inclusions were found widely distributed in the anterior horn and the anterior funiculus and anterolateral funiculus of the full spinal cord. Severe neuron loss and several morphological changes with gliosis in the anterior horn and severe loss of myelin in the anterior funiculus and anterolateral funiculus of the full spinal cord were observed in 4 cases of amyotrophic lateral sclerosis, 2 of which were found with Bunina bodies in neurons of the anterior horn. Three amyotrophic lateral sclerosis cases had ubiquitin-positive neuronal inclusions and TDP-43 positive neuronal and glial inclusions in the anterior horn at cervical and lumbar segments. A few argentophilic, tau positive neurofibrillary tangles (NFTs) and neuropil threads in the anterior horn at cervical and lumbar segments were found in 4 AD cases. Examination of spinal cord in 2 cases with Parkinson's disease combined with AD and 1 case with dementia with lewy body revealed severe neuron loss in the intermediolateral nucleus of thoracic segment, and a few synuclein positive lewy bodies and neuritis were also observed. There was mild neuron loss in the anterior horn at cervical and lumbar segments, along with some argentophilic, tau positive globous NFTs and many argentophilic, tau positive neutrophil threads were observed in 2 progressive supranuclear palsy cases and 1 corticobasal degeneration case. Each common neurodegenerative diseases of the spinal cord including multiple system strophy, amyotrophic lateral sclerosis and Parkinson's disease has its own specific histopathology and proteinopathy characteristics.

Re-evaluating the glio-centric view of multiple system atrophy by highlighting the neuronal involvement.

This scientific commentary refers to ‘Expanding the spectrum of neuronal pathology in multiple system atrophy’, by Cykowski et al. (doi:10.1093/brain/awv114). Multiple system atrophy has long been known to affect different populations of nerve cells in the brain, most often across multiple neural systems—hence the name. The degeneration of distinct but overlapping sets of neurons gives rise to what used to be thought of as three separate clinicopathological disorders—olivopontocerebellar atrophy, striatonigral degeneration and Shy-Drager syndrome—but is now recognized as two main subtypes: a parkinsonian subtype with striatal and nigral degeneration (MSA-P) and a cerebellar subtype with additional pontocerebellar degeneration (MSA-C) (Fanciulli and Wenning, 2015). Both subtypes feature autonomic dysfunction, with associated degeneration in a distributed network of autonomic brain regions (Fanciulli and Wenning, 2015). The most numerous and widespread pathology observed in the brains of such patients is fibrillar oligodendroglial cytoplasmic inclusions (GCI) (Papp and Lantos, 1994), largely composed of the neuronal protein α-synuclein (Gai et al. , 1998). In this regard, multiple system atrophy has been considered unique among neurodegenerative diseases in that it is dominated by proteinaceous inclusion pathology in the myelinating oligodendrocyte rather than in neurons. In this issue of Brain , Cykowski and co-workers assess the neuronal pathologies associated with multiple system atrophy, and conclude that they are more numerous and widespread than previously thought, and likely to have an important role in disease pathophysiology. Widespread neuronal inclusion pathologies have long been acknowledged in multiple system atrophy (Fig. 1A–C); however, their lower numbers and morphological diversity compared to GCIs (Papp and Lantos, 1994) has led to their virtual obscurity over the years. In fact, most studies have disregarded the neuronal inclusion pathology and focused instead on the role of GCIs in various aspects of the disease process. GCIs dominate white matter tracts in multiple …

Multiple system atrophy: genetic or epigenetic?

Multiple system atrophy (MSA) is a rare, late-onset and fatal neurodegenerative disease including multisystem neurodegeneration and the formation of α-synuclein containing oligodendroglial cytoplasmic inclusions (GCIs), which present the hallmark of the disease. MSA is considered to be a sporadic disease; however certain genetic aspects have been studied during the last years in order to shed light on the largely unknown etiology and pathogenesis of the disease. Epidemiological studies focused on the possible impact of environmental factors on MSA disease development. This article gives an overview on the findings from genetic and epigenetic studies on MSA and discusses the role of genetic or epigenetic factors in disease pathogenesis.

Multiple system atrophy.

Multiple system atrophy (MSA) is a rare adult-onset synucleinopathy associated with dysautonomia and the variable presence of poorly levodopa-responsive parkinsonism and/or cerebellar ataxia. Other clinical symptoms that can be associated with MSA include hyperreflexia, stridor, sleep apnea, and rapid eye movement sleep behavior disorder (RBD). Mean survival from time of diagnosis ranges between 6 to 10 years, and definitive diagnosis is made on autopsy with demonstration of oligodendroglial cytoplasmic inclusions consisting of fibrillar α-synuclein. Magnetic resonance imaging (MRI) may be positive for cruciform T2 hyperintensity within the pons (the "hot cross bun sign"), volume loss in the pons and cerebellum, and T2 signal loss in the dorsolateral putamen with hyperintense rim on fluid attenuated inversion recovery (FLAIR) sequencing. Although most cases are sporadic, genetic polymorphisms have been identified both in familial and sporadic cases of MSA, and influence observed phenotypes. Treatment is symptomatic, with both pharmacological and nonpharmacological strategies. There are currently no consensus guidelines on management. Current and future research is aimed at identifying biomarkers and developing disease-modifying therapies.

Loss of DJ‐1 protein stability and cytoprotective function by Parkinson's disease‐associated proline‐158 deletion

DJ-1 is a ubiquitous protein regulating cellular viability. Recessive mutations in the PARK7/DJ-1 gene are linked to Parkinson's disease (PD). Although the most dramatic L166P point mutation practically eliminates DJ-1 protein and function, the effects of other PD-linked mutations are subtler. Here, we investigated two recently described PD-associated DJ-1 point mutations, the A179T substitution and the P158Δ in-frame deletion. [A179T]DJ-1 protein was as stable as wild-type [wt]DJ-1, but the P158Δ mutant protein was less stable. In accord with the notion that dimer formation is essential for DJ-1 protein stability, [P158Δ]DJ-1 was impaired in dimer formation. Similar to our previous findings for [M26I]DJ-1, [P158Δ]DJ-1 bound aberrantly to apoptosis signal-regulating kinase 1. Thus, the PD-associated P158Δ mutation destabilizes DJ-1 protein and function. As there is also evidence for an involvement of DJ-1 in multiple system atrophy, a PD-related α-synucleinopathy characterized by oligodendroglial cytoplasmic inclusions, we studied an oligodendroglial cell line stably expressing α-synuclein. α-Synuclein aggregate dependent microtubule retraction upon co-transfection with tubulin polymerization-promoting protein p25α was ameliorated by [wt]DJ-1. In contrast, DJ-1 mutants including P158Δ failed to protect in this system, where we found evidence of apoptosis signal-regulating kinase 1 (ASK1) involvement. In conclusion, the P158Δ point mutation may contribute to neurodegeneration by protein destabilization and hence loss of DJ-1 function.

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

Multiple system atrophy (MSA) is a progressive late onset neurodegenerative α-synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of α-synuclein (αSYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar αSYN and dysfunction of the ubiquitin–proteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial αSYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human αSYN expression and determined the presence of MSA-like neurodegeneration in this model as compared to wild-type mice. PSI induced open field motor disability in transgenic αSYN mice but not in wild-type mice. The motor phenotype corresponded to progressive and selective neuronal loss in the striatonigral and olivopontocerebellar systems of PSI-treated transgenic αSYN mice. In contrast no neurodegeneration was detected in PSI-treated wild-type controls. PSI treatment of transgenic αSYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human αSYN in the cytoplasm of oligodendroglia, which resulted in myelin disruption and demyelination characterized by increased g-ratio. The oligodendroglial and myelin pathology was accompanied by axonal degeneration evidenced by signs of mitochondrial stress and dysfunctional axonal transport in the affected neurites. In summary, we provide new evidence supporting a primary role of proteolytic failure and suggesting a neurodegenerative pathomechanism related to disturbed oligodendroglial/myelin trophic support in the pathogenesis of MSA.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0977-5) contains supplementary material, which is available to authorized users.