Biology subjects

Sortwell, C. E.

Publications and source records attributed to Sortwell, C. E..

6 recordsLinked to original sources

bioRxiv2026

Complement Dysregulation During the Early Phases of Synucleinopathy

Parkinsons disease (PD) is characterized by progressive degeneration of nigrostriatal dopamine neurons and synucleinopathy, which is the accumulation of aggregated -synuclein (-syn). Increasing evidence implicates -syn-associated neuroinflammation as a contributor to PD pathogenesis; however, immune mechanisms linking synucleinopathy to neurodegeneration remain incompletely defined. Activation of the complement cascade occurs in PD and other neurodegenerative disorders, but most studies report complement activation after overt neurodegeneration, making it difficult to conclude if complement is directly activated by pathological -syn or secondarily following neurodegeneration. We used the rat -syn preformed fibril (PFF) mode, in vitro complement assays and human postmortem PD tissue to test whether pathological -syn directly activates complement prior to overt neurodegeneration. The -syn PFF model exhibits a protracted pathological time course and distinct temporal separation between peak -syn aggregation and nigrostriatal degeneration; thus we quantified complement expression, activation, and regulation during the aggregation phase. Synucleinopathy induced complement activation prior to nigrostriatal degeneration, including upregulation of components of both the classical (C1qa, C1r, C4b) and alternative (Cfd, Cfb) pathways, the anaphylatoxin (C3aR, C5aR) and phagocytic (CR3) complement receptors, and activation of complement C3. During early synucleinopathy, microglia upregulated C3 which significantly correlated with synucleinopathy burden across several brain regions, including the substantia nigra pars compacta (SNc) and cortex. Concurrently, complement regulatory proteins, including CD55, CD59, neuronal pentraxin-1 (Nptx1), and the neuronal pentraxin receptor were downregulated in the synucleinopathy-affected SNc. Importantly, increased levels of C1q and iC3b along with downregulation of CD55 and NPTX1 were also observed in human postmortem PD SNc, supporting the translational relevance of our findings. Mechanistically, we demonstrate that aggregated, but not monomeric, -syn directly binds C1q and activates the complement cascade in a C1q-dpendent manner. These data provide the first in vivo evidence that synucleinopathy triggers complement activation and dysregulation prior to neurodegeneration.

neuroscience↗

bioRxiv2024

The Impact of Brain-Derived Neurotrophic Factor rs6265 (Val66Met) Polymorphism on Therapeutic Electrical Stimulation for Peripheral Nerve Regeneration: A Preclinical Study of Therapy-Genotype Interactions

The Impact of Brain-Derived Neurotrophic Factor rs6265 (Val66Met) Polymorphism on Therapeutic Electrical Stimulation for Peripheral Nerve Regeneration: A Preclinical Study of Therapy-Genotype Interactions IntroductionPeripheral nerve injuries (PNIs) significantly impact patient quality of life. Therapeutic electrical stimulation (TES) shows promise in enhancing nerve regeneration, but outcomes vary widely. This study investigates the impact of the rs6265 single nucleotide polymorphism (SNP) on TES efficacy in a preclinical rat model and human stem cell-derived motor neurons. MethodsWild-type (WT) and rs6265 variant rats underwent sciatic nerve transection and received either TES or sham treatment. Muscle reinnervation was assessed through compound muscle action potentials and muscle fiber cross-sectional area. Isogenic human iPSC-derived motor neurons were used to study activity-dependent BDNF secretion. ResultsTES improved muscle reinnervation and fiber size in WT but not rs6265 allele carriers. rs6265 allele carriers exhibited impaired activity-dependent BDNF secretion in vitro. DiscussionThe rs6265 polymorphism influences TES efficacy, highlighting the need for personalized approaches in PNI treatment. These findings suggest that genetic screening could optimize therapeutic outcomes. Clinical RelevanceUnderstanding genetic factors affecting TES response can enhance treatment strategies for PNI, potentially improving patient recovery and reducing outcome variability.

neuroscience↗

bioRxiv2023

Developmental exposure to the Parkinson's disease-associated organochlorine pesticide dieldrin alters dopamine neurotransmission in α-synuclein pre-formed fibril (PFF)-injected mice

Parkinsons disease (PD) is the most common movement disorder and one of the fastest-growing neurological diseases worldwide. This increase outpaces the rate of aging and is most rapid in recently industrialized areas, suggesting the role of environmental factors. Consistent with this, epidemiological studies show an association between exposure to persistent organic pollutants and an increased risk of PD. When combined with post-mortem analysis and mechanistic studies, a role for specific compounds, including the organochlorine pesticide dieldrin, emerges. In mouse models, developmental dieldrin exposure causes male-specific exacerbation of neuronal susceptibility to MPTP and synucleinopathy. Specifically, our novel two-hit model combining developmental dieldrin exposure with the -synuclein (-syn) pre-formed fibril (PFF) model showed a male-specific exacerbation of PFF-induced increases in striatal dopamine (DA) turnover and motor deficits on the challenging beam 6 months post-PFF injection in male offspring developmentally exposed to dieldrin. Here, we hypothesized that alterations in DA handling contribute to the observed changes and assessed vesicular monoamine transporter 2 (VMAT2) function and DA release in this dieldrin/PFF two-hit model. Female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin or vehicle every 3 days, starting at 8 weeks of age by feeding and continuing throughout breeding, gestation, and lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections of -syn PFFs via stereotaxic surgery at 12 weeks of age and DA handling was assessed 4 months post-PFF injection via vesicular 3H-DA uptake assay and fast-scan cyclic voltammetry (FSCV). We observed no dieldrin-associated change in VMAT2 activity, but a dieldrin-induced increase in DA release in striatal slices in PFF-injected animals. These results suggest that developmental dieldrin exposure alters the dopaminergic response to synucleinopathy-triggered toxicity and supports our hypothesis that alterations in DA handling may underly the observed exacerbation of PFF-induced deficits in motor behavior and DA turnover. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/545967v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@d679deorg.highwire.dtl.DTLVardef@db0d70org.highwire.dtl.DTLVardef@14f368dorg.highwire.dtl.DTLVardef@1868894_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits

Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinsons disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the -synuclein (-syn)-preformed fibril (PFF) model, which better reflects the -syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to -syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3-4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated PFF-induced motor deficits on the challenging beam and increased DA turnover in the striatum 6 months after PFF injection. However, male offspring showed neither exacerbation of phosphorylated -syn (pSyn) aggregation in the substantia nigra (SN) at 1 or 2 months post-PFF injection, nor exacerbation of PFF-induced TH and NeuN loss in the SN 6 months post-PFF injection. Collectively, these data indicate that developmental dieldrin exposure produces a male-specific increase in neuronal vulnerability to synucleinopathy. This sex-specific result is consistent with both previous work in the MPTP model, our previously reported sex-specific effects of this exposure paradigm on the male and female epigenome, and the higher prevalence and more severe course of PD in males. The novel two-hit environmental toxicant/PFF exposure paradigm established in this project can be used to explore the mechanisms by which other PD-related exposures alter neuronal vulnerability to synucleinopathy in sporadic PD. HighlightsO_LIDevelopmental dieldrin exposure increases -syn-PFF-induced motor deficits C_LIO_LIDevelopmental dieldrin exposure increases PFF-induced deficits in DA handling C_LIO_LIDevelopmental dieldrin exposure does not affect PFF-induced loss of nigral neurons C_LIO_LIThis is a novel paradigm modeling how environmental factors increase risk of PD C_LIO_LIFemale mice show PFF-induced pathology, but no PFF-induced motor deficits. C_LI

neuroscience↗

bioRxiv2019

Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

Parkinsons disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding alpha-synuclein protein (aSyn), either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks of PD. Taken together, reduction of aSyn production may provide a disease-modifying therapy for PD. We show that antisense oligonucleotides (ASOs) reduce production of aSyn in rodent pre-formed fibril (PFF) models of PD. Reduced aSyn production leads to prevention and removal of established aSyn pathology and prevents dopaminergic cell dysfunction. In addition, we address the translational potential of the approach through characterization of human SNCA targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA ASOs throughout the non-human primate brain and a corresponding decrease in aSyn cerebral spinal fluid (CSF) levels. Taken together, these data suggest that by inhibiting production of aSyn it may be possible to reverse established pathology and thus supports the development of SNCA ASOs as a potentially disease modifying therapy for PD and related synucleinopathies.\n\nSummaryAntisense oligonucleotides designed against SNCA, which are progressing to the clinic, have the potential to be a disease modifying therapeutic for Parkinsons disease patients.

neuroscience↗

bioRxiv2019

Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson’s Disease

BackgroundThe transcription factor Nurr1 has been identified to be ectopically induced in the striatum of dyskinetic rodents expressing L-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression.\n\nMethodsWe used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with L-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single unit recordings and dendritic spine analyses in drug-naive rAAV-injected parkinsonian rats.\n\nResultsrAAV-GFP injected LID-resistant Lewis rats displayed mild LID and no induction of striatal Nurr1. However, Lewis rats transduced to overexpress Nurr1 developed severe LID. Nurr11 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in L-DOPA-naive rats striatal rAAV-Nurr1 overexpression 1) increased firing activity in dopamine-depleted striatal direct pathway neurons, and 2) decreased spine density and thin-spine morphology on striatal medium spiny neurons, mimicking changes seen in dyskinetic rats. Finally, we provide post-mortem evidence of Nurr1 expression in the striatum of L-DOPA treated PD patients.\n\nConclusionsOur data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.

neuroscience↗