ORCID Profile
0000-0002-0714-1063
Current Organisation
University of Tasmania
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Publisher: MDPI AG
Date: 23-07-2021
Abstract: Destabilization of faciliatory and inhibitory circuits is an important feature of corticomotor pathology in amyotrophic lateral sclerosis (ALS). While GABAergic inputs to upper motor neurons are reduced in models of the disease, less understood is the involvement of peptidergic inputs to upper motor neurons in ALS. The neuropeptide Y (NPY) system has been shown to confer neuroprotection against numerous pathogenic mechanisms implicated in ALS. However, little is known about how the NPY system functions in the motor system. Herein, we investigate post-synaptic NPY signaling on upper motor neurons in the rodent and human motor cortex, and on cortical neuron populations in vitro. Using immunohistochemistry, we show the increased density of NPY-Y1 receptors on the soma of SMI32-positive upper motor neurons in post-mortem ALS cases and SOD1G93A excitatory cortical neurons in vitro. Analysis of receptor density on Thy1-YFP-H-positive upper motor neurons in wild-type and SOD1G93A mouse tissue revealed that the distribution of NPY-Y1 receptors was changed on the apical processes at early-symptomatic and late-symptomatic disease stages. Together, our data demonstrate the differential density of NPY-Y1 receptors on upper motor neurons in a familial model of ALS and in ALS cases, indicating a novel pathway that may be targeted to modulate upper motor neuron activity.
Publisher: Wiley
Date: 08-2021
DOI: 10.1111/JNC.15125
Abstract: Neuropeptide Y (NPY) is an endogenous peptide of the central and enteric nervous systems which has gained significant interest as a potential neuroprotective agent for treatment of neurodegenerative disease. Amyotrophic lateral sclerosis (ALS) is an aggressive and fatal neurodegenerative disease characterized by motor deficits and motor neuron loss. In ALS, recent evidence from ALS patients and animal models has indicated that NPY may have a role in the disease pathogenesis. Increased NPY levels were found to correlate with disease progression in ALS patients. Similarly, NPY expression is increased in the motor cortex of ALS mice by end stages of the disease. Although the functional consequence of increased NPY levels in ALS is currently unknown, NPY has been shown to exert a erse range of neuroprotective roles in other neurodegenerative diseases through modulation of potassium channel activity, increased production of neurotrophins, inhibition of endoplasmic reticulum stress and autophagy, reduction of excitotoxicity, oxidative stress, neuroinflammation and hyperexcitability. Several of these mechanisms and signalling pathways are heavily implicated in the pathogenesis of ALS. Therefore, in this review, we discuss possible effects of NPY and NPY‐receptor signalling in the ALS disease context, as determining NPY’s contribution to, or impact on, ALS disease mechanisms will be essential for future studies investigating the NPY system as a therapeutic strategy in this devastating disease. image
Publisher: Springer Science and Business Media LLC
Date: 06-03-2022
DOI: 10.1007/S12035-022-02742-5
Abstract: Amyotrophic lateral sclerosis (ALS) attacks the corticomotor system, with motor cortex function affected early in disease. Younger females have a lower relative risk of succumbing to ALS than males and older females, implicating a role for female sex hormones in disease progression. However, the mechanisms driving this dimorphic incidence are still largely unknown. We endeavoured to determine if estrogen mitigates disease progression and pathogenesis, focussing upon the dendritic spine as a site of action. Using two-photon live imaging we identify, in the prp TDP-43 A315T mouse model of ALS, that dendritic spines in the male motor cortex have a reduced capacity for remodelling than their wild-type controls. In contrast, females show higher capacity for remodelling, with peak plasticity corresponding to highest estrogen levels during the estrous cycle. Estrogen manipulation through ovariectomies and estrogen replacement with 17β estradiol in vivo was found to significantly alter spine density and mitigate disease severity. Collectively, these findings reveal that synpatic plasticity is reduced in ALS, which can be amelioriated with estrogen, in conjuction with improved disease outcomes.
Publisher: JMIR Publications Inc.
Date: 12-12-2017
DOI: 10.2196/JMIR.8046
Publisher: Wiley
Date: 29-08-2023
DOI: 10.1002/ACN3.51885
Abstract: Neuropeptide Y (NPY) is a 36 amino acid peptide widely considered to provide neuroprotection in a range of neurodegenerative diseases. In the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), recent evidence supports a link between NPY and ALS disease processes. The goal of this study was to determine the therapeutic potential and role of NPY in ALS, harnessing the brain‐targeted intranasal delivery of the peptide, previously utilised to correct motor and cognitive phenotypes in other neurological conditions. To confirm the association with clinical disease characteristics, NPY expression was quantified in post‐mortem motor cortex tissue of ALS patients and age‐matched controls. The effect of NPY on ALS cortical pathophysiology was investigated using slice electrophysiology and multi‐electrode array recordings of SOD1 G93A cortical cultures in vitro. The impact of NPY on ALS disease trajectory was investigated by treating SOD1 G93A mice intranasally with NPY and selective NPY receptor agonists and antagonists from pre‐symptomatic and symptomatic phases of disease. In the human post‐mortem ALS motor cortex, we observe a significant increase in NPY expression, which is not present in the somatosensory cortex. In vitro, we demonstrate that NPY can ameliorate ALS hyperexcitability, while brain‐targeted nasal delivery of NPY and a selective NPY Y1 receptor antagonist modified survival and motor deficits specifically within the symptomatic phase of the disease in the ALS SOD1 G93A mouse. Taken together, these findings highlight the capacity for non‐invasive brain‐targeted interventions in ALS and support antagonism of NPY Y1Rs as a novel strategy to improve ALS motor function.
Publisher: Wiley
Date: 2019
No related grants have been discovered for Courtney Clark.