Biology subjects

Bol, J. G.

Publications and source records attributed to Bol, J. G..

6 recordsLinked to original sources

bioRxiv2025

Multiscale analysis of myelin alterations in skin biopsies from synucleinopathies.

Loss of myelin and demyelination play a role in the pathophysiology of Parkinsons disease (PD) and related neurodegenerative diseases, but little is known about the ultrastructure of the myelin-axon unit in the peripheral nervous system of subjects diseased with synucleinopathies. We here present an analysis of the myelin ultrastructure and the myelin protein abundance that characterize myelinated axons of nerve fiber bundles in cervical skin biopsies of 45 pathologically confirmed PD, DLB, MSA and non-neurological control donors. We calculated a myelin damage score and classified over 1100 myelin sheaths by looking at myelin fragmentation and swellings with correlative light and electron microscopy. We found a higher load of myelin damage in the PD compared to MSA and control groups. Quantification with ELISA did not reveal any differences in myelin protein zero (MPZ) concentrations in skin tissue homogenates between synucleinopathies. The observed structural abnormalities in the myelin sheaths may help to discriminate among subjects with synucleinopathies and control subjects and to understand the involvement of the peripheral innervation in the diseases. Our multiscale analysis of peripheral nerves highlights their potential as future biomarkers for the detection and differentiation of synuclein diseases.

neuroscience↗

bioRxiv2024

Ultrastructural diversity of alpha-Synuclein pathology in the post-mortem brain of Parkinson patients: implications for Lewy Body formation

Lewy bodies, the defining pathological feature of Parkinsons disease, are intraneuronal inclusions enriched in aggregated alpha-synuclein (Syn). We used correlative light and electron microscopy to selectively investigate phosphorylated Syn (SynpS129)-positive inclusions in the substantia nigra of end-stage postmortem Parkinsons disease brain. Here we show that somatic SynpS129 inclusions in nigral dopaminergic neurons are consistently fibrillar, whereas the membranous-type inclusions are restricted to neuritic processes. These neuritic inclusions displayed marked ultrastructural heterogeneity, ranging from predominantly membranous to mixed membranous-fibrillar forms. The selective targeting of defined inclusions enabled detailed structural characterization of Lewy pathology, rather than quantitative or disease-stage comparisons. Our findings highlight clear ultrastructural differences between somatic and neuritic SynpS129 pathology and demonstrate the structural complexity and heterogeneity of Lewy pathology in human Parkinsons disease brain.

neuroscience↗

bioRxiv2023

Altered TFEB subcellular localization in nigral dopaminergic neurons of subjects with prodromal, sporadic and GBA-related Parkinson's disease and Dementia with Lewy bodies

Transcription factor EB is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis of GBA-related and sporadic Parkinsons disease (PD) and dementia with Lewy bodies (DLB). TFEB activation at the lysosomal level results in its translocation from the cytosol to the nucleus. Here, we aimed at investigating whether TFEB subcellular localization is altered in post-mortem human brain of aged individuals with either prodromal PD/DLB (incidental Lewy body disease, iLBD, N=3), GBA-related PD/DLB (N=9) or sPD/DLB (N=9), compared to control subjects (N=12). We scanned nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the observed TFEB subcellular localization patterns. In line with previous studies, we observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both sporadic and GBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn cytopathology and in cases carrying pathogenic GBA variants. Interestingly, we further observed previously unidentified TFEB-immunopositive somatic clusters in human brain dopaminergic neurons and in human embryonic stem cell (hESC)-derived neurons, which localized at the Golgi apparatus. The TFEB clustering was more frequently observed and more severe in iLBD, sPD/DLB and GBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons but also in neurons without apparent cytopathology. Notably, increased frequency of cytoplasmic TFEB clusters in aSyn-negative cells correlated with reduced total GBA enzymatic activity and higher Braak LB stage. In the studied patient population, altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected CLEAR genes, indicating a possible early dysfunction of lysosomal regulation. Overall, these findings suggest the early cytoplasmic TFEB retention and accumulation at the Golgi prior pSer129 aSyn accumulation in incidental, GBA-related and sporadic PD/DLB and indicate TFEB as potential as early therapeutic target for synucleinopathies

neuroscience↗

bioRxiv2022

Nigral pathology contributes to microstructural integrity of striatal and frontal tracts in Parkinson's disease

BackgroundMotor and cognitive impairment in Parkinsons disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant -synuclein accumulation. Diffusion MRI can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood. ObjectiveTo unravel the pathological substrate underlying microstructural alterations of the SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD. MethodsCombining post-mortem in-situ MRI and histopathology, T1-weighted and diffusion MRI of 9 PD, 6 PD with dementia (PDD), 5 dementia with Lewy bodies (DLB), and 10 control donors were collected. From MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129--synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively. ResultsCompared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased FA of the SN and SN-caudate nucleus tract was associated with SN dopaminergic loss, while increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load. ConclusionsIn PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology.

neuroscience↗

bioRxiv2022

Cortical distribution of neurofilaments associates with pathological hallmarks and MRI measures of atrophy and diffusivity in Parkinson's disease

Increased neurofilament levels in biofluids, commonly used as a proxy for axonal degeneration in the brain, have been found in Parkinsons disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB), and correlate with MRI biomarkers. The aim of the current study was to unravel the regional distribution of cortical neurofilaments and their association with pathology load and MRI measures of atrophy and diffusivity in the post-mortem brain. Using a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pSer129 alpha-synuclein (pSer129-Syn), p-tau, and amyloid-beta, together with neurofilament light-chain (NfL) and phosphorylated neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in 7 cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models. Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was mainly increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. Increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-Syn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB. Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increasing pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.

neuroscience↗

bioRxiv2021

Amyloid-beta, p-tau, and reactive microglia load are correlates of MRI cortical atrophy in Alzheimer's disease

INTRODUCTIONThe aim of this study was to identify the histopathological correlates of MRI cortical atrophy in (a)typical Alzheimers disease (AD) donors. METHODS19 AD and 10 control donors underwent post-mortem in-situ 3T-3DT1-MRI, from which cortical thickness was calculated. Upon subsequent autopsy, 21 cortical brain regions were selected and immunostained for amyloid-beta, phosphorylated-tau, and reactive microglia. MRI-pathology associations were assessed using linear mixed models. Post-mortem MRI was compared to ante-mortem MRI when available. RESULTSHigher amyloid-beta load weakly correlated with a higher cortical thickness globally. Phosphorylated-tau strongly correlated with cortical atrophy in temporo-frontal regions. Reactive microglia load strongly correlated with cortical atrophy in the parietal region. Post-mortem scans showed high concordance with ante-mortem scans acquired <1 year before death. DISCUSSIONDistinct histopathological markers differently correlate with cortical atrophy, highlighting their different roles in the neurodegenerative process. This study contributes in understanding the pathological underpinnings of MRI atrophy patterns.

neuroscience↗