Physiology - Journal Articles

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    Characterization of Fabry disease-associated lyso-Gb3 on mouse colonic ion transport and motility
    (American Physiological Society, 2024) Delprete, Cecilia; Uhlig, Friederike; Caprini, Marco; Hyland, Niall P.; Science Foundation Ireland; Fondazione Cassa di Risparmio in Bologna; Università di Bologna; Horizon 2020
    Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency in α-galactosidase A leading to the accumulation of globotriaosylceramide (Gb3) and subsequent increase in globotriaosylsphingosine (lyso-Gb3) in different cells and organs, including the gastrointestinal (GI) tract. GI symptoms represent some of the earliest manifestations of FD and significantly impact quality of life. The origin of these symptoms is complex, and the exact mechanisms remain poorly understood. Here, we sought to determine whether lyso-Gb3 contributes to the pathophysiology of GI symptoms associated with FD by examining its effects on mouse colonic ion transport and motility ex vivo using Ussing chambers and organ baths respectively. Lyso-Gb3 significantly increased colonic baseline short-circuit current (ISC). This increase in ISC was insensitive to inhibition of the cystic fibrosis transmembrane conductance regulator and Na-K-Cl cotransporter 1 suggesting that the increase in ISC is Cl- ion independent. This response was also insensitive to inhibition with the neurotoxin, tetrodotoxin. Additionally, pretreatment with lyso-Gb3 did not significantly influence subsequent responses to either veratridine or capsaicin implying that the response to lyso-Gb3 does not involve the enteric nervous system. In terms of colonic motility, lyso-Gb3 did not significantly influence colonic tone, spontaneous contractility or cholinergic-induced contractions. These data suggest that lyso-Gb3, significantly influences ion transport in mouse colon, but that accumulation of Gb3 may be a pre-requisite for the more pronounced disturbances in GI physiology characteristic of FD.
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    The impact of fatigue on people with Fibromyalgia Syndrome: A survey
    (Wiley, 2023-07-21) McToal, Martina; McVeigh, Rachel Christina; McVeigh, Joseph G.; Fibromyalgia Support Northern Ireland
    Introduction: Fibromyalgia syndrome (FMS) is a common pain syndrome associated with fatigue and anxiety. The aim of this survey was to determine the impact of fatigue on the quality of life (QoL) of people with FMS and to explore the relationships between fatigue, pain, and anxiety. Methods: A postal survey was conducted among support groups. Demographic data were collected and participants were asked to complete the Multi-dimensional Assessment of Fatigue Scale (MAF) and two visual analog scales (VAS) measuring pain and anxiety. Data were analysed using descriptive statistics, and relationships between variables were explored using Pearson's correlation coefficient and Fisher's Exact Probability Test. Ethical approval was granted from Ulster University's research ethics committee. Results: A response rate of 52.5% was achieved (105/200). Fatigue was found to severely impact the QoL of those with FMS. From the MAF, a mean Global Fatigue Index score of 40.7 (range 1 = no fatigue—50 = severe fatigue) was calculated. Fatigue was significantly associated with both pain (r = 0.674) and anxiety (r = 0.546) (both p values < 0.0001), and no significant relationship was found between the duration of FMS and fatigue (r = 0.106; p = 0.320). Conclusion: Fatigue has a major impact on the QoL of patients with FMS. There is a strong relationship between fatigue and other variables such as pain and anxiety. However, there is no relationship between the time since diagnosis and fatigue experienced. Fatigue management should feature highly in any treatment programme for those with FMS.
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    Gene co-expression analysis of the human substantia nigra identifies ZNHIT1 as an SNCA co-expressed gene that protects against α-synuclein-induced impairments in neurite growth and mitochondrial dysfunction in SH-SY5Y cells
    (Springer, 2022-02-17) McCarthy, Erin; Barron, Aaron; Morales-Prieto, Noelia; Mazzocchi, Martina; McCarthy, Cathal M.; Collins, Louise M.; Sullivan, Aideen M.; O’Keeffe, Gerard W.; Science Foundation Ireland; Irish Research Council; HORIZON EUROPE Marie Sklodowska-Curie Actions
    Parkinson’s disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn). Since current PD therapies do not prevent neurodegeneration, there is a need to identify therapeutic targets that can prevent α-Syn-induced reductions in neuronal survival and neurite growth. We hypothesised that genes that are normally co-expressed with the α-Syn gene (SNCA), and whose co-expression pattern is lost in PD, may be important for protecting against α-Syn-induced dopaminergic degeneration, since broken correlations can be used as an index of functional misregulation. Gene co-expression analysis of the human SN showed that nuclear zinc finger HIT-type containing 1 (ZNHIT1) is co-expressed with SNCA and that this co-expression pattern is lost in PD. Overexpression of ZNHIT1 was found to increase deposition of the H2A.Z histone variant in SH-SY5Y cells, to promote neurite growth and to prevent α-Syn-induced reductions in neurite growth and cell viability. Analysis of ZNHIT1 co-expressed genes showed significant enrichment in genes associated with mitochondrial function. In agreement, bioenergetic state analysis of mitochondrial function revealed that ZNHIT1 increased cellular ATP synthesis. Furthermore, α-Syn-induced impairments in basal respiration, maximal respiration and spare respiratory capacity were not seen in ZNHIT1-overexpressing cells. These data show that ZNHIT1 can protect against α-Syn-induced degeneration and mitochondrial dysfunction, which rationalises further investigation of ZNHIT1 as a therapeutic target for PD.
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    Peripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson’s disease
    (Elsevier, 2022-02-25) Mazzocchi, Martina; Goulding, Susan R.; Morales-Prieto, Noelia; Foley, Tara; Collins, Louise M.; Sullivan, Aideen M.; O'Keeffe, Gerard W.; Science Foundation Ireland; Irish Research Council; HORIZON EUROPE Marie Sklodowska-Curie Actions
    Parkinson’s disease (PD) is a neurodegenerative disorder characterised by nigrostriatal dopaminergic (DA) neurodegeneration. There is a critical need for neuroprotective therapies, particularly those that do not require direct intracranial administration. Small molecule inhibitors of histone deacetylases (HDIs) are neuroprotective in in vitro and in vivo models of PD, however it is unknown whether Class IIa-specific HDIs are neuroprotective when administered peripherally. Here we show that 6-hydroxydopamine (6-OHDA) treatment induces protein kinase C (PKC)-dependent nuclear accumulation of the Class IIa histone deacetylase (HDAC)5 in SH-SY5Y cells and cultured DA neurons in vitro. Treatment of these cultures with the Class IIa-specific HDI, MC1568, partially protected against 6-OHDA-induced cell death. In the intrastriatal 6-OHDA lesion in vivo rat model of PD, MC1568 treatment (0.5 mg/kg i.p.) for 7 days reduced forelimb akinesia and partially protected DA neurons in the substantia nigra and their striatal terminals from 6-OHDA-induced neurodegeneration. MC1568 treatment prevented 6-OHDA-induced increases in microglial activation in the striatum and substantia nigra. Furthermore, MC1568 treatment decreased 6-OHDA-induced increases in nuclear HDAC5 in nigral DA neurons. These data suggest that peripheral administration of Class IIa-specific HDIs may be a potential therapy for neuroprotective in PD.
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    Bioinformatics and immunohistochemical analyses support preserved expression of glial cell line–derived neurotrophic factor receptor RET in Parkinson's
    (Wiley, 2023-07-21) Doran, Conor Giles; Wilson, Fionnuala; Goulding, Susan R.; Mazzocchi, Martina; Collins, Louise M.; Sullivan, Aideen M.; O'Keeffe, Gerard W.; Cure Parkinson's Trust; Science Foundation Ireland