Tick Borne Encephalitis (TBE) is endemic to an increasing number of countries and is a common cause of meningoencephalitis in Europe and Asia making any potential complications of the disease increasingly relevant to clinicians. We present, what is to our knowledge, the second reported case of N-methyl-d-aspartate receptor (NMDAR) encephalitis following Tick Borne Encephalitis (TBE) in a 47-year-old Lithuanian man. The case provides further evidence of TBE being a possible trigger of NMDAR encephalitis and highlights the importance of being aware of symptoms of autoimmune encephalitis in patients with infectious encephalitis.
Background and Objectives The two most common autoimmune encephalitides (AE), N -methyl-D-Aspartate receptor (NMDAR) and Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis, have been known for more than a decade. Nevertheless, no well-established biomarkers to guide treatment or estimate prognosis exist. Neurofilament light chain (NfL) has become an unspecific screening marker of axonal damage in CNS diseases, and has proven useful as a diagnostic and disease activity marker in neuroinflammatory diseases. Only limited reports on NfL in AE exist. We investigated NfL levels at diagnosis and follow-up in NMDAR and LGI1-AE patients, and evaluated the utility of CSF-NfL as a biomarker in AE. Methods Patients were included from the National Danish AE cohort (2009-present) and diagnosed based upon autoantibody positivity and diagnostic consensus criteria. CSF-NfL was analyzed by single molecule array technology. Clinical and diagnostic information was retrospectively evaluated and related to NfL levels at baseline and follow-up. NMDAR-AE patients were subdivided into: idiopathic/teratoma associated or secondary NMDAR-AE (post-viral or concomitant with malignancies/demyelinating disease). Results A total of 74 CSF samples from 53 AE patients (37 NMDAR and 16 LGI1 positive) were included in the study. Longitudinal CSF-NfL levels was measured in 21 patients. Median follow-up time was 23.8 and 43.9 months for NMDAR and LGI1-AE respectively. Major findings of this study are: i) CSF-NfL levels were higher in LGI1-AE than in idiopathic/teratoma associated NMDAR-AE at diagnosis; ii) CSF-NfL levels in NMDAR-AE patients distinguished idiopathic/teratoma cases from cases with other underlying etiologies (post-viral or malignancies/demyelinating diseases) and iii) Elevated CSF-NfL at diagnosis seems to be associated with worse long-term disease outcomes in both NMDAR and LGI1-AE. Discussion CSF-NfL measurement may be beneficial as a prognostic biomarker in NMDAR and LGI1-AE, and high CSF-NfL could foster search for underlying etiologies in NMDAR-AE. Further studies on larger cohorts, using standardized methods, are warranted.
Abstract Mutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson’s disease (PD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial PD upon parkin loss-of-function remains unknown. Cultures of isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockout (KO) enable mechanistic studies of the effect of parkin deficiency in human dopaminergic neurons. We used such cells to investigate the impact of PARK2 KO on the lysosomal compartment and found a clear link between parkin deficiency and lysosomal alterations. PARK2 KO neurons exhibited a perturbed lysosomal morphology with enlarged electron-lucent lysosomes and an increased lysosomal content, which was exacerbated by mitochondrial stress and could be ameliorated by antioxidant treatment. We also found decreased lysosomal enzyme activity and autophagic perturbations, suggesting an impairment of the autophagy-lysosomal pathway in parkin-deficient cells. Interestingly, activity of the GBA-encoded enzyme, β-glucocerebrosidase, was increased, suggesting the existence of a compensatory mechanism. In conclusion, our data provide a unique characterization of the morphology, content, and function of lysosomes in PARK2 KO neurons and reveal an important new connection between mitochondrial dysfunction and lysosomal dysregulation in PD pathogenesis.
Abstract PARK2 (parkin) mutations cause early onset of autosomal recessively inherited Parkinson’s disease (PD). Parkin is an ubiquitin E3 ligase and has been reported to participate in several cellular functions, including mitochondrial homeostasis. However, the specific metabolomic changes caused by parkin depletion remain largely unknown. Human induced pluripotent stem cells (iPSCs) with PARK2 knockout (KO) provide a valuable model for studying parkin dysfunction in dopaminergic neurons. In the current study, we used isogenic iPSCs to investigate the effect of parkin loss-of-function by comparative metabolomics analysis. The metabolomic profile of the PARK2 KO neurons differed substantially from that of healthy controls. We found increased tricarboxylic acid (TCA) cycle activity, perturbed mitochondrial ultrastructure connected with ATP depletion, glycolysis dysregulation with lactate accumulation, and elevated levels of short- and long-chain carnitines. These mitochondrial and energy perturbations in the PARK2 KO neurons were combined with increased levels of oxidative stress and a decreased anti-oxidative response. In conclusion, our data describe a unique metabolomic profile associated with parkin dysfunction, demonstrating several PD-related cellular defects. Our findings support and expand previously described PD phenotypic features and show that combining metabolomic analysis with an iPSC-derived dopaminergic neuronal model of PD is a valuable approach to obtain novel insight into the disease pathogenesis.
Abstract Cerebral organoids (CBOs) are generated from pluripotent stem cells that undergo neuroectoderm specification and neuronal differentiation in three dimensions. The developing neurons in CBOs migrate and self-organize into cerebral cortex-like layers, mimicking human brain development. CBOs develop according to intrinsic signaling mechanisms and offer unique insights into mechanisms of early human brain development. This process requires coordinated spatiotemporal regulation of protein expression and function, where the latter can be achieved by post-translational modifications (PTMs) on proteins. Despite the importance of proteins in brain development and function, profiling of protein abundance and the involvement of PTMs in CBO development remain underexplored. To gain insight into protein and PTM abundance in CBOs, we performed a high-resolution temporal analysis of CBOs up to day 200 using proteomics, PTMomics and metabolomics. We quantified more than 9,300 proteins and various neurodevelopmentally relevant PTMs (including phosphorylation, lysine acetylation, sialylated N-glycosylation, and cysteine modifications). We demonstrate that protein abundance and dynamic PTMs show significant temporal changes during CBO development related to neuronal differentiation and energy metabolism, whereas calcium signaling is mainly regulated by dynamic PTMs. We further show that synaptic protein content correlated with neurotransmitter levels, and we detected astroglia beyond day 100. Lastly, comparative analysis showed proteomic similarities between CBOs and human fetal brain tissue, supporting the physiological relevance of CBOs. Overall, our study presents a temporal atlas of protein and PTM abundance in CBOs and provides a valuable resource for studying neurodevelopment in neural organoids.
Diagnosis of paraneoplastic neurologic syndromes (PNS) requires an understanding of the clinical, immunologic and oncologic heterogeneity. The 2004 PNS criteria were partially outdated due to advances in the field, and updated consensus criteria for PNS have been proposed in 2021, including the PNS-Care score for assessment of PNS probability. Furthermore, knowledge on the limitations of autoantibody testing is crucial to ensure accurate interpretation. This review presents the updated diagnostic criteria for PNS, in a Danish context.
The heterogeneity of autoantibody targets in autoimmune encephalitides presents a challenge for understanding cellular and humoral pathophysiology, and the development of new treatment strategies. Thus, current treatment aims at autoantibody removal and immunosuppression, and is primarily based on data generated from other autoimmune neurological diseases and expert consensus. There are many subtypes of autoimmune encephalitides, which now entails both diseases with autoantibodies targeting extracellular antigens and classical paraneoplastic syndromes with autoantibodies targeting intracellular antigens. Here, we review the current knowledge of molecular and cellular effects of autoantibodies associated with autoimmune encephalitis, and evaluate the evidence behind the proposed pathophysiological mechanisms of autoantibodies in autoimmune encephalitis.
Parkinson's disease is a neurodegenerative disease resulting in degeneration of midbrain dopaminergic neurons. Exploratory studies using human foetal tissue or predifferentiated stem cells have suggested that intracerebral transplantation of dopaminergic precursor cells may become an effective treatment for patients with Parkinson's disease. However, strategies for dopaminergic stem cell differentiation vary widely in efficiency, and better methods still need to be developed. Hypoxia Inducible Factor 1 (HIF-1) is a transcription factor involved in the regulation of genes important for cellular adaption to hypoxia and low glucose supply. HIF-1 is to a large degree regulated by the availability of oxygen as in its presence, the subunit HIF-1α is degraded by HIF prolyl hydroxylase enzymes (HPHs). Stabilization of HIF-1α through inhibition of HPHs has been shown to increase dopaminergic differentiation of stem cells and to protect dopaminergic neurons against neurotoxins. This study investigated the effects of noncompetitive (FG-0041) and competitive (Compound A and JNJ-42041935) HIF-1α stabilizing compounds on the dopaminergic differentiation of human neural stem cells. Treatment with all HPH inhibitors at high oxygen tension (20%) resulted in HIF-1α stabilization as assessed by immunocytochemistry for HIF-1α and detection of increased levels of vascular endothelial growth factor in the conditioned culture medium. Following 10 days of HIF-1α stabilization, the cultures displayed a slightly reduced proliferative activity and significantly increased relative levels of tyrosine hydroxylase-positive dopaminergic neurons. In conclusion, HIF-1α stabilization may represent a promising strategy for the generation of dopaminergic neurons intended for use in experimental in vitro studies and cell replacement therapies.
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