Summary De novo mutation plays an important role in Autism Spectrum Disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes, and may also include nucleotide-substitution hotspots. We investigated global patterns of germline mutation by whole genome sequencing of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely throughout the genome (by 100-fold) and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Dense clusters of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing datasets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans.
Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less severe than in Alzheimer’s disease. Previously, we found that familial Parkinson’s disease-linked human mutant A53T αS causes aberrant localization of the microtubule-associated protein tau to postsynaptic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the synaptic and memory deficits in a mouse model of α-synucleinopathy (TgA53T) are mediated by tau. TgA53T mice exhibit progressive memory deficits associated with postsynaptic deficits in the absence of obvious neuropathological and neurodegenerative changes in the hippocampus. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau−/−), achieved by mating TgA53T mice to mouse tau-knockout mice, completely ameliorates cognitive dysfunction and concurrent synaptic deficits without affecting αS expression or accumulation of selected toxic αS oligomers. Among the known tau-dependent effects, memory deficits in TgA53T mice were associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau−/− mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results directly implicate tau as a mediator of specific human mutant A53T αS-mediated abnormalities related to deficits in hippocampal neurotransmission and suggest a mechanism for memory impairment that occurs as a consequence of synaptic dysfunction rather than synaptic or neuronal loss. We hypothesize that these initial synaptic deficits contribute to network hyperexcitability which, in turn, exacerbate cognitive dysfunction. Our results indicate that these synaptic changes present potential therapeutic targets for amelioration of memory deficits in α-synucleinopathies.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02032-w) contains supplementary material, which is available to authorized users.
Abnormalities in ␣-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). Because ␣-synuclein is highly concentrated within presynaptic terminals, presynaptic dysfunction has been proposed as a potential pathogenic mechanism. Here, we report novel, tau-dependent, postsynaptic deficits caused by A53T mutant ␣-synuclein, which is linked to familial PD. We analyzed synaptic activity in hippocampal slices and cultured hippocampal neurons from transgenic mice of either sex expressing human WT, A53T, and A30P ␣-synuclein. Increased ␣-synuclein expression leads to decreased spontaneous synaptic vesicle release regardless of genotype. However, only those neurons expressing A53T ␣-synuclein exhibit postsynaptic dysfunction, including decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. We also found that long-term potentiation and spatial learning were impaired by A53T ␣-synuclein expression. Mechanistically, postsynaptic dysfunction requires glycogen synthase kinase 3-mediated tau phosphorylation, tau mislocalization to dendritic spines, and calcineurin-dependent AMPA receptor internalization. Previous studies reveal that human A53T ␣-synuclein has a high aggregation potential, which may explain the mutation's unique capacity to induce postsynaptic deficits. However, patients with sporadic PD with severe tau pathology are also more likely to have early onset cognitive decline. Our results here show a novel, functional role for tau: mediating the effects of ␣-synuclein on postsynaptic signaling. Therefore, the unraveled tau-mediated signaling cascade may contribute to the pathogenesis of dementia in A53T ␣-synuclein-linked familial PD cases, as well as some subgroups of PD cases with extensive tau pathology.
Background Colony‐stimulating factor‐1 receptor (CSF1R)‐related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease‐modifying treatment. Objective The objective of this study was to determine the effect of HSCT on disease progression. Methods We collected all available clinical data from a cohort of 7 patients with CSF1R‐related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board‐certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI). Results Our patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow‐up time (median, 11; range, 2–27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden. Conclusions This is the largest series of patients with CSF1R‐related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease‐modifying therapy for CSF1R‐related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease‐specific therapies. © 2021 International Parkinson and Movement Disorder Society
Background Neuronal dysfunction and degeneration linked to α-synuclein (αS) pathology is thought to be responsible for the progressive nature of Parkinson’s disease and related dementia with Lewy bodies. Studies have indicated bidirectional pathological relationships between αS pathology and tau abnormalities. We recently showed that A53T mutant human αS (HuαS) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in the development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set out to determine the role of tau in the onset and progression of αS pathology (α-synucleinopathy) using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression. Methods Transgenic mice expressing A53T mutant HuαS (TgA53T) were crossed with mTau−/− mice to generate TgA53T/mTau−/−. To achieve more uniform induction of α-synucleinopathy in mice, we used intramuscular injections of αS preformed fibrils (PFF) in non-transgenic (nTg), TgA53T, TgA53T/mTau−/−, and mTau−/− mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. Results Loss of tau expression significantly delayed the onset of motor deficits in the TgA53T model and the progression of α-synucleinopathy disease, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 αS aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, was prevented with tau removal. Conclusions Collectively, our data suggest that tau is likely acting downstream of αS pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in α-synucleinopathies to identify novel disease-modifying therapeutic strategies.
Parkinson's disease (PD) is one of the most common progressive, systemic, and incurable neurodegenerative disorders with a high mortality rate and an increased risk of premature death when compared to the general population. 1 Actually, FIG 1. Hypothetical model for CSF1R-related leukoencephalopathy disease progression and proposed optimal timing for hematopoietic stem cell transplantation (HSCT) for patients with known CSF1R pathogenic variants. The gray shading corresponds with the optimal timing for HSCT; that is, darker shading correlates with better disease stages during which to consider HSCT. Years are based on published averages of symptom onset and disease duration. 4 Activities of daily living (ADL), mild cognitive impairment (MCI), mild behavioral impairment (MBI), and Sundal magnetic resonance imaging severity scale Total Score(SSS Tot ). 3 [Color figure can be viewed at wileyonlinelibrary.com]
ImportanceType 2 diabetes (T2D) and heart failure (HF) prevalence are rising in the US. Although glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve outcomes for these conditions, high out-of-pocket costs may be associated with reduced medication adherence.ObjectiveTo compare 1-year adherence to GLP1-RA and SGLT2i therapies by prescription co-payment level in individuals with T2D and/or HF.Design, Setting, and ParticipantsThis retrospective cohort study used deidentified data from Optum Insight’s Clinformatics Data Mart Database of enrollees with commercial and Medicare health insurance plans. Individuals aged 18 years or older with T2D and/or HF who had a prescription claim for a GLP1-RA or SLGT2i from January 1, 2014, to September 30, 2020, were included.ExposuresPrescription co-payment, categorized as low (<$10), medium ($10 to<$50), and high (≥$50).Main Outcomes and MeasuresThe primary outcome was medication adherence, defined as a proportion of days covered (PDC) of 80% or greater at 1 year. Logistic regression models were used to examine the association between co-payment and adherence, adjusting for patient demographics, medical comorbidities, and socioeconomic factors.ResultsA total of 94 610 individuals (mean [SD] age, 61.8 [11.4] years; 51 226 [54.1%] male) were prescribed GLP1-RA or SGLT2i therapy. Overall, 39 149 individuals had a claim for a GLP1-RA, of whom 25 557 (65.3%) had a PDC of 80% or greater at 1 year. In fully adjusted models, individuals with a medium (adjusted odds ratio [AOR], 0.62; 95% CI, 0.58-0.67) or high (AOR, 0.47; 95% CI, 0.44-0.51) co-payment were less likely to have a PDC of 80% or greater with a GLP1-RA compared with those with a low co-payment. Overall, 51 072 individuals had a claim for an SGLT2i, of whom 37 339 (73.1%) had a PDC of 80% or greater at 1 year. Individuals with a medium (AOR, 0.67; 95% CI, 0.63-0.72) or high (AOR, 0.68; 95% CI, 0.63-0.72) co-payment were less likely to have a PDC of 80% or greater with an SGLT2i compared with those with a low co-payment.Conclusions and RelevanceIn this cohort study of individuals with T2D and/or HF, 1-year adherence to GLP1-RA or SGLT2i therapies was highest among individuals with a low co-payment. Improving adherence to guideline-based therapies may require interventions that reduce out-of-pocket prescription costs.
Introduction: Diabetes and heart failure (HF) rates are rising. Glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with improved outcomes in these conditions. Out-of-pocket cost may reduce medication adherence. We examined the association of medication copayment with 1-year adherence to these agents in individuals with diabetes and HF. Hypothesis: Individuals with high copayments have reduced adherence to GLP1RAs and SGLT2is. Methods: Using the Optum de-identified Clinformatics Data Mart Database, individuals with diabetes and HF and ≥12 months of enrollment with a GLP1RA or SLGT2i claim from 2014-2021 were included. We defined adherence as the proportion of days covered (PDC) ≥80%. We used multivariable logistic regression models to examine the adjusted odds of adherence by copayment level, defined as low (<$10 USD), medium ($10-<$50), and high (≥$50). Covariates included patient socioeconomic and clinical comorbidities. Results: We identified 94,610 individuals (age 61.8±11.4 years; 45.9% female) prescribed GLP1RAs or SGLT2is from 1/1/2014-9/30/2020, Overall, 39,149 individuals had a claim for a GLP1RA, of whom 25,557 (65.3%) had PDC ≥80%. In fully adjusted models, individuals with medium (adjusted odds ratio, aOR 0.61, 95% CI, 0.57-0.66) and high copayment (aOR 0.48, 95% CI, 0.44-0.51) were less likely to have PDC ≥80% with GLPRAs compared to those with low copayment ( Figure ). Overall, 51,072 individuals had a claim for an SGLT2i, of whom 37,339 (73.1%) individuals had PDC ≥80% at 1 year. Individuals with medium (aOR 0.67, 95% CI, 0.62-0.71) and high copayment (aOR 0.69, 95% CI, 0.64-0.74) were less likely to have PDC ≥80% with SGLT2is compared to those with low copayment. Conclusion: In a large cohort of individuals with diabetes and HF, 1-year adherence to GLP1RA or SGLT2i therapies was highest among individuals with low copayment. Improving adherence to guideline-based therapies requires interventions that reduce prescription costs.
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