Pumilio2-deficient mice show a predisposition for epilepsy

Epilepsy is a neurological disease that is caused by abnormal hypersynchronous activities of neuronal ensembles leading to recurrent and spontaneous seizures in human patients. Enhanced neuronal excitability and a high level of synchrony between neurons seem to trigger these spontaneous seizures. The molecular mechanisms, however, regarding the development of neuronal hyperexcitability and maintenance of epilepsy are still poorly understood. Here, we show that pumilio RNA-binding family member 2 (Pumilio2;Pum2) plays a role in the regulation of excitability in hippocampal neurons of weaned and 5-month-old male mice. Almost complete deficiency of Pum2 in adult Pum2 gene-trap mice (Pum2 GT) causes misregulation of genes involved in neuronal excitability control. Interestingly, this finding is accompanied by the development of spontaneous epileptic seizures in Pum2 GT mice. Furthermore, we detect an age-dependent increase in Scn1a (Na(v)1.1) and Scn8a (Na(v)1.6) mRNA levels together with a decrease in Scn2a (Na(v)1.2) transcript levels in weaned Pum2 GT that is absent in older mice. Moreover, field recordings of CA1 pyramidal neurons show a tendency towards a reduced paired-pulse inhibition after stimulation of the Schaffer-collateral-commissural pathway in Pum2 GT mice, indicating a predisposition to the development of spontaneous seizures at later stages. With the onset of spontaneous seizures at the age of 5 months, we detect increased protein levels of Na(v)1.1 and Na(v)1.2 as well as decreased protein levels of Na(v)1.6 in those mice. In addition, GABA receptor subunit alpha-2 (Gabra2) mRNA levels are increased in weaned and adult mice. Furthermore, we observe an enhanced GABRA2 protein level in the dendritic field of the CA1 subregion in the Pum2 GT hippocampus. We conclude that altered expression levels of known epileptic risk factors such as Na(v)1.1, Na(v)1.2, Na(v)1.6 and GABRA2 result in enhanced seizure susceptibility and manifestation of epilepsy in the hippocampus. Thus, our results argue for a role of Pum2 in epileptogenesis and the maintenance of epilepsy

Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments

Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular

SARS-CoV-2 and neurodegenerative diseases: what we know and what we don't

Infection of the CNS with the SARS-CoV-2 can occur via different routes and results in para- or post-infectious manifestations with a variety of neurological symptoms. In patients with neurodegenerative diseases, SARS-CoV-2 is often associated with a higher fatality rate, which is a relevant problem in increasingly older populations. Apart from the direct consequences of an infection in patients with neurodegenerative diseases, indirect consequences of the pandemic such as limited access to care facilities and treatment have negative effects on the course of these chronic disorders. The occurrence of long-lasting neurological symptoms after infection with SARS-CoV-2 indicates a prolonged impact on the CNS. However, while it is known that SARS-CoV-2 affects neuronal populations that are relevant in the pathogenesis of neurodegenerative diseases, it is yet unclear whether an infection with SARS-CoV-2 is sufficient to trigger neurodegeneration. Reflecting on the impact of SARS-CoV-2 on neurodegeneration, we provide a concise overview on the current knowledge of SARS-CoV-2-induced pathology in the CNS and discuss yet open questions in the field

Impact of the COVID-19 Pandemic on Patients with Parkinson’s Disease from the Perspective of Treating Physicians—A Nationwide Cross-Sectional Study

The COVID-19 pandemic has posed challenges to maintaining medical care for patients with Parkinson’s disease (PD). The Parkinson’s Disease during the COVID-19 Pandemic (ParCoPa) survey was conducted as an online, nationwide, cross-sectional survey from December 2020 to March 2021 and aimed to assess the impact of the pandemic on the medical care of PD patients from the physicians’ perspective. Invitations containing a randomly generated registration code were mailed to healthcare professionals from sixty-seven specialty centers in Germany. Confounders for the worsening of subjective treatment quality, perceived health risk due to the profession, and adequate protective measures against SARS-CoV-2 were assessed using logistic regression analysis. Of all forty physicians who responded, 87.5% reported a worsening of motor and nonmotor symptoms in their patients, 97.5% experienced cancellation of appointments, and difficulties in organizing advanced and supplementary therapies were reported by over 95%. Participants offered alternative consultation options, mostly in the form of telephone (77.5%) or online (64.1%) consultations, but telephone consultations were the most accepted by patients (“broadly accepted”, 40.0%). We identified pandemic-related deficits in providing care for patients with PD and areas of improvement to ensure continued care for this vulnerable patient population

Cerebral venous sinus thrombosis after ChAdOx1 nCov-19 vaccination with a misleading first cerebral MRI scan

Vaccine-induced immune thrombotic thrombocytopenia (VITT) and cerebral venous sinus thrombosis (CVST) have been recently described as rare complications following vaccination against SARS-CoV-2 with vector vaccines. We report a case of a young woman who presented with VITT and cerebral CVST 7 days following vaccination with ChAdOx1 nCov-19 (AstraZeneca). While the initial MRI was considered void of pathological findings, MRI 3 days later revealed extensive CVST of the transversal and sigmoidal sinus with intracerebral haemorrhage. Diagnostic tests including a platelet-factor-4-induced platelet activation assay confirmed the diagnosis of VITT. Treatment with intravenous immunoglobulins and argatroban resulted in a normalisation of platelet counts and remission of CVST

Reduced tear fluid production in neurological diseases: a cohort study in 708 patients

BackgroundTear fluid (TF) production is an important component of normal ocular function. It is regulated by parasympathetic and sympathetic innervation. Because parasympathetic nerve fibers originate in the brainstem, pathology in this brain region may affect TF production. For example, a reduction in TF production has been described in patients with Parkinson's disease (PD).MethodsTF was collected at one center from 772 individuals, 708 of which were patients with different neurological diseases, and 64 healthy controls. Wetting lengths (WL) were recorded using Schirmer test strips with a collection time of 10 min.ResultsWL correlated negatively with age and was significantly reduced in subgroups of patients with neurodegenerative diseases (NDDs) (PD, Amyotrophic lateral sclerosis (ALS), other motor neuron diseases (MNDs)), as well as inflammatory/autoimmune/infectious central nervous system (CNS) diseases and vascular CNS diseases (VCDs), even if corrected for age or sex. While temperature had a significant negative effect on TF production, other environmental factors, such as hours of sunlight and humidity, did not.ConclusionWL was altered in many neurological diseases compared to healthy controls. Most importantly, we observed a reduction of WL in NDDs, independent of age or sex. This study highlights the potential of WL as an easily obtainable parameter and suggests functional alterations in the autonomic innervation in various neurological disorders

Long-Lasting Impact of the COVID-19 Pandemic on Patients with Parkinson's Disease and Their Relatives

Background The coronavirus disease 2019 (COVID-19) pandemic has heavily impacted medical care of patients with Parkinson's disease (PwP).Objective To assess the longitudinal impact of the COVID-19 pandemic on PwP and their relatives in Germany.Methods Two online, nationwide, cross-sectional surveys were conducted from December 2020 to March 2021 and from July to September 2021.Results A total of 342 PwP and 113 relatives participated. Despite partial resumption of social and group activities, healthcare was continuously disrupted during times of loosened restrictions. Respondents' willingness to use telehealth infrastructure increased, yet the availability remained low. PwP reported worsened symptoms and further deterioration during the pandemic, resulting in an increase in new symptoms and relatives' burden. We identified patients at particular risk: young patients and those with long disease duration.Conclusions The COVID-19 pandemic persistently disrupts the care and quality of life of PwP. Although willingness to use telemedicine services has increased, its availability needs to be improved

Parkinson's disease therapy: what lies ahead?

The worldwide prevalence of Parkinson's disease (PD) has been constantly increasing in the last decades. With rising life expectancy, a longer disease duration in PD patients is observed, further increasing the need and socioeconomic importance of adequate PD treatment. Today, PD is exclusively treated symptomatically, mainly by dopaminergic stimulation, while efforts to modify disease progression could not yet be translated to the clinics. New formulations of approved drugs and treatment options of motor fluctuations in advanced stages accompanied by telehealth monitoring have improved PD patients care. In addition, continuous improvement in the understanding of PD disease mechanisms resulted in the identification of new pharmacological targets. Applying novel trial designs, targeting of pre-symptomatic disease stages, and the acknowledgment of PD heterogeneity raise hopes to overcome past failures in the development of drugs for disease modification. In this review, we address these recent developments and venture a glimpse into the future of PD therapy in the years to come