Glial dysfunction in the pathogenesis of α-synucleinopathies: emerging concepts

Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are adult onset neurodegenerative disorders characterised by prominent intracellular α-synuclein aggregates (α-synucleinopathies). The glial contribution to neurodegeneration in α-synucleinopathies was largely underestimated until recently. However, brains of PD and DLB patients exhibit not only neuronal inclusions such as Lewy bodies or Lewy neurites but also glial α-synuclein aggregates. Accumulating experimental evidence in PD models suggests that astrogliosis and microgliosis act as important mediators of neurodegeneration playing a pivotal role in both disease initiation and progression. In MSA, oligodendrocytes are intriguingly affected by aberrant cytoplasmic accumulation of α-synuclein (glial cytoplasmic inclusions, Papp-Lantos bodies). Converging evidence from human postmortem studies and transgenic MSA models suggests that oligodendroglial dysfunction both triggers and exacerbates neuronal degeneration. This review summarises the wide range of responsibilities of astroglia, microglia and oligodendroglia in the healthy brain and the changes in glial function associated with ageing. We then provide a critical analysis of the role of glia in α-synucleinopathies including putative mechanisms promoting a chronically diseased glial microenvironment which can lead to detrimental neuronal changes, including cell loss. Finally, major therapeutic strategies targeting glial pathology in α-synucleinopathies as well as current pitfalls for disease-modification in clinical trials are discussed.     

Lovastatin ameliorates α-synuclein accumulation and oxidation in transgenic mouse models of α-synucleinopathies

Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many diseases including Dementia with Lewy Bodies (DLB) and Parkinson's Disease (PD), collectively termed the α-synucleinopathies. The mechanisms underlying α-syn aggregation remain elusive though emerging science has hypothesized that the interaction between cholesterol and α-syn may play a role. Cholesterol has been linked to α-synucleinopathies by recent work suggesting cholesterol metabolites appear to accelerate α-syn fibrillization. Consistent with these findings, cholesterol-lowering agents have been demonstrated to reduce α-syn accumulation and the associated neuronal pathology in vitro. In this context, this study sought to investigate the in vivo effects of the cholesterol synthesis inhibitor lovastatin on α-syn aggregation in two different transgenic (Tg) mouse models that neuronally overexpress human α-syn. Lovastatin-treated mice displayed significantly reduced plasma cholesterol levels and levels of oxidized cholesterol metabolites in the brain in comparison to saline-treated controls. Immunohistochemical analysis demonstrated a significant reduction of neuronal α-syn aggregates and α-syn immunoreactive neuropil in the temporal cortex of lovastatin-treated Tg mice in comparison to saline-treated α-syn Tg controls. Consistently, immunoblot analysis of mouse brain homogenates showed a reduction in levels of total and oxidized α-syn in lovastatin-treated α-syn Tg mice in comparison to saline-treated α-syn Tg controls. The reduced α-syn accumulation in lovastatin-treated mice was associated with abrogation of neuronal pathology. The results from this study demonstrate that lovastatin administration can reduce α-syn aggregation and associated neuropathology and support the possibility that treatment with cholesterol-lowering agents may be beneficial for patients with PD and/or DLB.     

Multiple system atrophy as emerging template for accelerated drug discovery in α-synucleinopathies

There is evidence that the α-synucleinopathies Parkinson's disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P) overlap at multiple levels. Both disorders are characterized by deposition of abnormally phosphorylated fibrillar α-synuclein within the central nervous system suggesting shared pathophysiological mechanisms. Despite the considerable clinical overlap in the early disease stages, MSA-P, in contrast to PD, is fatal and rapidly progressive. Moreover recent clinical studies have shown that surrogate markers of disease progression can be quantified easily and may reliably depict the rapid course of MSA. We therefore posit that, MSA-P may be exploited as a filter barrier in the development of disease-modifying therapeutic strategies targeting common pathophysiological mechanisms of α-synucleinopathies. This approach might reduce the number of negative phase III clinical trials, and, in turn, shift the available resources to earlier development stages, thereby increasing the number of candidate compounds validated.     

The prodromal stage of psychotic illness: observation,detection or intervention?

Accurate identification of individuals in the earliest symptomatic stages of psychosis offers perhaps the best hope for more effective treatment strategies. Recently, research clinics have been set up to identify and possibly treat individuals who are seen as being at high risk of a psychotic disorder. However, there have been concerns about beginning treatment at this stage. We need to address these concerns so that individuals who are at risk of psychosis come to no harm, yet the development of potential interventions is not delayed. This article briefly reviews some of the newer developments and concerns in this area of psychosis research.     

α-Synuclein pathology affecting Bergmann glia of the cerebellum in patients with α-synucleinopathies

We carried out immunohistochemical examinations of the brains (cerebella) of patients who had suffered from Parkinson's disease (PD), diffuse Lewy body disease (DLBD) or multiple system atrophy (MSA), using antibodies specific for alpha-synuclein. Alpha-synuclein-positive doughnut-shaped structures were found occasionally in the cerebellar molecular layer in some of these patients. Double-labeling immunofluorescence and immunoelectron microscopy studies revealed that these alpha-synuclein-positive doughnut-shaped structures were located in the glial fibrillary acidic protein-positive radial processes of Bergmann glia, corresponding to the outer area of Lewy body-like inclusions, and consisted of granulo-filamentous structures. These findings indicate that, although not frequently, Bergmann glia of the cerebellum are also the targets of alpha-synuclein pathology in alpha-synucleinopathies such as PD, DLBD and MSA.     

Can premorbid and prodromal markers associated with psychosis be utilized for early detection and secondary prevention of schizophrenia?

The rationale for identifying markers of latent schizophrenia is the evidence that early treatment speeds remission and lessens long-term deterioration. Unfortunately hovever, although the childhood and adolescence of individual psychotics often reveal premorbid deviations from established norms, while epidemiological studies identify cognitive performance and social adjustment as potential premorbid markers, such signs vary widely and no typical prodrome has been identified. Illness-related events or behaviors are not the only factors precipitating the transition from premorbid to prodrome: educational and socioeconomic status are also involved, it follows that there is a controversy surrounding the secondary prevention of schizophrenia: because of the poor specificity of premorbid and prodromal markers, treating such patients implies thai an unacceptably high proportion of individuals who will not ultimately develop florid schizophrenia will be exposed to stigma of a provisional diagnosis of severe mental illness as well as to the adverse effects of treatment Schizophrenia, therefore, is an aggravated illustration of the dilemmas facing much preventive therapy.     

Diagnostic value of surrogate CSF biomarkers for Creutzfeldt–Jakob disease in the era of RT-QuIC

Journal of Neurology - Prion real-time quaking-induced conversion (RT-QuIC) is emerging as the most potent assay for the in vivo diagnosis of Creutzfeldt–Jakob disease (CJD), but its full...     

Associations of sleep disorders with cerebrospinal fluid α-synuclein in prodromal and early Parkinson’s disease

Journal of Neurology - Our aim is to investigate the associations of sleep disorders with cerebrospinal fluid (CSF) α-synuclein (α-syn) in healthy controls (HCs), and patients with...     

Can we improve the diagnostic efficiency and predictive power of prodromal symptoms for schizophrenia?

Prodromal symptoms and other variables for a sample of 200 young people who had experienced a first-onset functional psychosis, were analyzed to examine their diagnostic efficiency and predictive power in relation to a diagnosis of schizophrenia. Two different techniques were utilized to generate optimal cut-off points for a number of prodromal symptoms, and optimal decision rules to maximize diagnostic efficiency. The product of the chance-corrected sensitivity and specificity, or the area under the QROC curve, was used to assess the predictive efficiency of a number of prodromal variables, DSM-III-R prodromal variables, pre-psychotic deterioration, pre-morbid functioning, and prodromal duration. The SPAN technique generated a decision rule that performed equivalently to the single variable 'duration of prodrome'. Implications of these results for future research are discussed.     

Toll-like receptor 4 deficiency facilitates α-synuclein propagation and neurodegeneration in a mouse model of prodromal Parkinson's disease

The evidence linking innate immunity mechanisms and neurodegenerative diseases is growing, but the specific mechanisms are incompletely understood. Experimental data suggest that microglial TLR4 mediates the uptake and clearance of α-synuclein also termed synucleinophagy. The accumulation of misfolded α-synuclein throughout the brain is central to Parkinson's disease (PD). The distribution and progression of the pathology is often attributed to the propagation of α-synuclein. Here, we apply a classical α-synuclein propagation model of prodromal PD in wild type and TLR4 deficient mice to study the role of TLR4 in the progression of the disease. Our data suggest that TLR4 deficiency facilitates the α-synuclein seed spreading associated with reduced lysosomal activity of microglia. Three months after seed inoculation, more pronounced proteinase K-resistant α-synuclein inclusion pathology is observed in mice with TLR4 deficiency. The facilitated propagation of α-synuclein is associated with early loss of dopamine transporter (DAT) signal in the striatum and loss of dopaminergic neurons in substantia nigra pars compacta of TLR4 deficient mice. These new results support TLR4 signaling as a putative target for disease modification to slow the progression of PD and related disorders.     

Schizotypal personality disorder or prodromal symptoms of schizophrenia?

Schizotypal personality disorder shares some attenuated phenotypic features with schizophrenia, but represents an independent syndrome. In contrast, prodromal symptoms of schizophrenia represent early warning signs of the impending onset of schizophrenia. Although these constructs are intended to reflect independent syndromes, self-report instruments measuring these constructs assess similar symptoms. It does not appear that existing research has examined the relative discriminant validity of screening instruments for these syndromes. A sample of 998 young adults (68% female; 73% Caucasian), within the age of risk for schizophrenia (ages 18–34; mean 20.4 ± 2.2), met validity criteria after completing online versions of the Abbreviated Schizotypal Personality Questionnaire (SPQ-B) and the 24-item Abbreviated Youth Psychosis at Risk Questionnaire (Y-PARQ-B). Based on clinical cut-off scores used in previous research, 5.2% were [only] considered at heightened risk for psychosis (potentially prodromal), 3.4% had [only] schizotypal personality features, and 2.9% met criteria for both constructs (75% of individuals meeting cutoff for one measure did not meet criteria for the other). Males and younger participants scored significantly higher on both measures. The total scores from the SPQ-B and Y-PARQ-B showed a significant positive correlation (r_s = .66, p < .001, R² = .43); however, 57% of the variance was not shared between the measures. Of the three SPQ-B subscales, Cognitive–Perceptual showed the strongest correlation with Y-PARQ-B. Results suggest that the SPQ-B and Y-PARQ-B have moderate discriminate validity between the overlapping, yet distinct, constructs of schizotypal personality and heightened risk of developing psychosis (potentially prodromal).     

Pathological properties of the Parkinson’s disease-associated protein DJ-1 in α-synucleinopathies and tauopathies: relevance for multiple system atrophy and Pick’s disease

Mutations in the PARK7 gene DJ-1 are associated with recessive hereditary Parkinsons disease (PD). Fibrillar inclusions of -synuclein comprise the neuropathological hallmarks of PD and related Lewy body diseases as well as multiple system atrophy (MSA). Moreover, neuronal and glial inclusions containing tau have been observed in -synucleinopathy patients. Using a collection of antibodies against DJ-1, we have performed a comprehensive investigation of DJ-1 in -synucleinopathies and tauopathies. DJ-1 was abundantly expressed in reactive astrocytes of patients with neurodegenerative diseases. Likewise, DJ-1 antiserum immunostained reactive astrocytes that became abundant with disease progression in the brain stem of transgenic mice expressing mutant [A30P]-synuclein. Human Lewy bodies as well as Lewy body-like inclusions in the -synuclein transgenic mice were DJ-1 negative. Neuronal tau inclusions were DJ-1 immunopositive in Picks disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimers disease. In addition, we found DJ-1-immunopositive glial inclusions in CBD, PSP and MSA. Biochemical extraction experiments revealed the specific presence of insoluble, modified DJ-1 in PiD and MSA. Our results suggest that DJ-1 is up-regulated in reactive astrocytes as well as in neuronal and glial cells with specific -synucleinopathy and tauopathy.     

In vivo detection of iron and neuromelanin by transcranial sonography – a new approach for early detection of substantia nigra damage

Summary. In more than 90% of patients with idiopathic Parkinson’s disease (PD) hyperechogenicity of the substantia nigra (SN) can be found by transcranial sonography (TCS) as a typical, stable sign. Animal experiments provided first evidence that SN hyperechogenicity may be associated with increased tissue iron levels. Two consecutive studies revealed the same association in human brain. Postmortem brains of 60 subjects without clinical signs for Parkinson’s disease during life time at different ages were scanned by ultrasound with planimetric measurement of the echogenic area of the SN. Afterwards the SN was dissected and used for histological examination and determination of iron content in all brains as well as ferritin and neuromelanin content in 40 brains. A significant positive correlation was found between the echogenic area of the SN and the concentration of iron, H- and L-ferritins. A multivariate analysis performed considering the iron content showed a significant negative correlation between echogenicity and neuromelanin content of the SN. Iron staining confirmed the biochemical findings. In PD a typical loss of neuromelanin and increase of iron is observed in this brain area. However, it is not clear yet, whether iron accumulation is a primary cause or a secondary phenomenon in the disease process. Screening of genes involved in brain iron metabolism showed a significant association of some sequence variations of the ceruloplasmin gene with PD. Others were associated with the ultrasound marker for increased iron levels in both PD patients and control subjects. As SN hyperechogenicity is typical for PD or subjects with a preclinical impairment of the nigrostriatal system, these findings indicate that TCS enables the detection of increased iron and decreased neuromelanin levels at the SN, even before the clinical manifestation of PD.