Biology subjects

Svenningsson, P.

Publications and source records attributed to Svenningsson, P..

25 records · Page 2Linked to original sources

bioRxiv2023

Cortex-wide topography of 1/f-exponent in Parkinson's disease

Parkinsons Disease causes progressive and debilitating changes to the brain as well as to the mind. While the diagnostic hallmark features are the characteristic movement-related symptoms, the disease also causes decline in sensory processing, cognitive, emotional performance and most patients develop dementia over time. The extent of symptoms and the brain-wide projections of neuromodulators such as dopamine suggest that many brain regions are simultaneously affected in Parkinsons disease. To characterise such disease-related and brain-wide changes in neuronal function, we performed a source level analysis of resting state magnetoencephalogram (MEG) from two groups: Parkinsons disease patients and healthy controls. Besides standard spectral analysis, we quantified the aperiodic component of the neural activity by fitting a power law ({kappa}/f {lambda}) to the MEG spectrum and then studied its relationship with age and UPDRS. Consistent with previous results, the most significant spectral changes were observed in the high theta/low alpha band (7-10 Hz) in all brain regions. Furthermore, analysis of the aperiodic part of the spectrum showed that, in all but frontal regions, {lambda} was significantly larger in Parkinsons disease patients than in control subjects. Our results indicate for the first time that Parkinsons disease is associated with significant changes in population activity across the whole neocortex. Surprisingly, even early sensory areas showed a significantly larger {lambda} in patients than in healthy controls. Moreover, {lambda} was not affected by the L-dopa medication. Finally, {lambda} was positively correlated with patient age but not with UPDRS-III (summary measure of motor symptoms clinical rating). Because {lambda} is closely associated excitationinhibition balance, our results propose new hypotheses about manifestation of Parkinsons disease in cortical networks.

neuroscience↗

bioRxiv2022

SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF

The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed the interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogenous nucleation (HEN). In the current study, we show that the incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid (CSF) leads to the amyloid aggregation of several proteins known to be involved in neurodegenerative diseases, such as: APLP1 (amyloid beta precursor like protein 1), ApoE, clusterin, 2-macroglobulin, PGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3, transthyretin and vitronectin. Importantly, UV-inactivation of SARS-CoV-2 does not affect its ability to induce amyloid aggregation, as amyloid formation is dependent on viral surface catalysis via HEN and not its ability to replicate. Additionally, viral amyloid induction led to a dramatic drop in the soluble protein concentration in the CSF. Our results show that viruses can physically induce amyloid aggregation of proteins in human CSF and result in soluble protein depletion, and thus providing a potential mechanism that may account for the association between persistent and latent/reactivating brain infections and neurodegenerative diseases. Significance StatementViruses have generally been excluded from the etiology of amyloid pathologies based on the assumption that amyloid formation requires a proteinaceous conformational template (a prion) to form. Here we show that neuroinvasive viruses induce amyloid aggregation of a plethora of proteins in human CSF even after UV inactivation. Our work illustrates that viruses can induce amyloid aggregation of endogenous human proteins in their native environment by acting as physical catalysts of amyloid nucleation and phase transition. Demonstrating this direct mechanistic link, which is independent of templating, can help better understand the link between viruses and neurodegenerative disorders, especially in the post-COVID-19 era.

microbiology↗

bioRxiv2022

Single cell transcriptomics reveals correct developmental dynamics and high-quality midbrain cell types by improved hESC differentiation.

Stem cell technologies provide new opportunities for modeling cells in the healthy and diseased states and for regenerative medicine. In both cases developmental knowledge as well as the quality and molecular properties of the cells are essential for their future application. In this study we identify developmental factors important for the differentiation of human embryonic stem cells (hESCs) into midbrain dopaminergic (mDA) neurons. We found that Laminin-511, and dual canonical and non-canonical WNT activation followed by GSK3{beta} inhibition plus FGF8b, improved midbrain patterning. In addition, mDA neurogenesis and differentiation was enhanced by activation of liver X receptors and inhibition of fibroblast growth factor signaling. Moreover, single-cell RNA-sequencing analysis revealed a developmental dynamics similar to that of the endogenous human ventral midbrain and the emergence of high quality molecularly-defined midbrain cell types, including mDA neurons that become functional. Thus, our study identifies novel factors important for human midbrain development and opens the door for a future application of molecularly-defined hESC-derived midbrain cell types in Parkinsons disease.

neuroscience↗

bioRxiv2022

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

How neurons in the CNS can maintain cellular identity over an entire lifespan remains largely unknown. Here we show that long-term maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2-component, Eed, in these neurons, resulted in global loss of H3K27me3, followed by a gradual activation of genes harbouring both H3K27me3 and H3K9me3 modifications. Notably, H3K9me3 was also lost at these PRC2-targets prior to gene activation. Neuronal survival was not compromised, instead there was a reduction in subtype specific gene expression as well as a progressive impairment of dopaminergic or serotonergic neuronal function leading to behavioural deficits characteristic of Parkinsons disease (PD) or mood disorders, respectively. Single cell analysis revealed an unexpected subtype specific vulnerability to loss of PRC2-repression in dopamine neurons of the substantia nigra, the neurons primarily affected in PD. Taken together, our study reveals that a PRC2-dependent non-permissive chromatin state is essential to maintain subtype identity and function of dopaminergic and serotonergic neurons.

neuroscience↗

bioRxiv2021

Cerebrospinal fluid amyloid beta and glial fibrillary acidic protein concentrations in Huntingtons disease

IntroductionHuntingtons disease (HD) is a genetic incurable lethal disease. Biomarkers are needed for objective assessment of disease progression. Evidence supports both complex protein aggregation and astrocyte activation in HD. This study assesses the 42 amino acid long amyloid beta (A{beta}42) and glial fibrillary acidic protein (GFAP) as potential biomarkers in the cerebrospinal fluid (CSF) of HD mutation carriers. MethodsCSF was obtained from manifest HD patients (ManHD), premanifest HD-gene-expansion carriers (PreHD) and gene-negative controls (controls). Disease Burden Score (DBS) and Total Functional Capacity (TFC) were calculated. Protein concentrations were measured by enzyme-linked immunosorbent assays (ELISA) and intergroup differences were analysed using Mann-Whitney U test. Spearman correlations were calculated to assess disease stage association. Age-adjustment was included in the statistical tests. ResultsThe study enrolled 27 ManHD and 13 PreHD subjects. The number of controls differed in the analysis of A{beta}42 and GFAP (n = 19, and 8 respectively). A{beta}42 levels were higher in ManHD (mean 741 ng/l, SD 361) compared with PreHD (mean 468 ng/l, SD 184) (p = 0.025). Likewise GFAP concentration was higher in ManHD (mean 435 ng/l, SD 255) compared with both PreHD (mean 266 ng/l, SD 92.4)(p = 0.040) and controls (mean 208 ng/l, SD 83.7)(p = 0.011). GFAP correlated with DBS (r = 0.361, p = 0.028), TFC (r = - 0.463, p = 0.005), and 5-year risk of onset in PreHD (r = 0.694, p = 0.008). In contrast, there was no correlation between A{beta}42 concentration and DBS, TFC or 5-year risk of onset. ConclusionCSF A{beta}42 levels did not correlate with disease stage suggesting no A{beta}aggregation in HD. GFAP is a potential biomarker in HD with association to disease stage. Validation in larger HD cohorts and potential correlations with clinical phenotype would be of interest.

neuroscience↗

bioRxiv2019

Reduction of spontaneous cortical beta bursts in Parkinson’s disease is linked to symptom severity

Parkinsons disease is characterized by a gradual loss of dopaminergic neurons, which are associated with altered neuronal activity in the beta band (13-30 Hz). Assessing beta band activity typically involves transforming the time-series to get the power of the signal in the frequency-domain. Such transformation assumes that the time-series can be reduced to a combination of steady-state sine-and cosine waves. However, recent studies have suggested that this approach masks relevant biophysical features in the beta band activity--for example, that the beta band exhibits transient bursts of high-amplitude activity.\n\nIn an exploratory study we used magnetoencephalography (MEG) to record cortical beta band activity to characterize how spontaneous cortical beta bursts manifest in Parkinsons patients ON and OFF dopaminergic medication, and compare this to matched healthy controls. From three minutes of MEG data, we extracted the time-course of beta band activity from the sensorimotor cortex and characterized high-amplitude epochs in the signal to test if they exhibited burst like properties. We then compared the rate, duration, inter-burst interval, and peak amplitude of the high-amplitude epochs between the Parkinsons patients and healthy controls.\n\nOur results show that Parkinsons patients OFF medication had a 6-17% lower beta bursts rate compared to healthy controls, while both the duration and the amplitude of the bursts were the same for Parkinsons patients and healthy controls and medicated state of the Parkinsons patients. These data thus support the view that beta bursts are fundamental underlying features of beta band activity, and show that changes in cortical beta band power in PD can be explained primarily by changes in the underlying burst rate. Importantly, our results also revealed a relationship between beta bursts rate and motor symptom severity in PD: a lower burst rate scaled with increased in severity of bradykinesia and postural/kinetic tremor. Beta burst rate might thus serve as neuromarker for Parkinsons disease that can help in the assessment of symptom severity in Parkinsons disease or evaluate treatment effectiveness.

neuroscience↗

bioRxiv2018

Attenuated post-movement beta rebound in Parkinson’s disease to proprioceptive afferent feedback

Motor symptoms are defining traits in the diagnosis of Parkinsons disease (PD). A crucial component in motor function and control of movements is the integration of efferent signals from the motor network to the peripheral motor system, and afferent proprioceptive sensory feedback. Previous studies have indicated abnormal movement-related cortical oscillatory activity in PD, but the role of the proprioceptive afference on abnormal oscillatory activity in PD has not been elucidated. In the present study, we examine the role of proprioception by studying the cortical processing of proprioceptive stimulation in PD patients, ON/OFF levodopa medication, as compared to that of healthy controls (HC). We used a proprioceptive stimulator that generated precisely controlled passive movements of the index finger and measured the induced cortical oscillatory responses following the proprioceptive stimulation using magnetoencephalography (MEG). Both PD patients and HC showed a typical initial mu/beta-band (8-30 Hz) desynchronization during the passive movement. However, the subsequent beta rebound after the passive movement that was apparent in HC was much attenuated and almost absent in PD patients. Furthermore, we found no difference in the degree of beta rebound attenuation between patients ON and OFF levodopa medication. Our results hence demonstrate a disease-related deterioration in cortical processing of proprioceptive afference in PD, and further suggest that such disease-related loss of proprioceptive function is due to processes outside the dopaminergic system affected by levodopa medication.

neuroscience↗