Physiology - Journal Articles

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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
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    Human α‐synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing
    (Wiley, 2024-03-26) Morales‐Prieto, Noelia; Bevans, Rebekah; O'Mahony, Adam; Barron, Aaron ; Doran, Conor Giles ; McCarthy, Erin ; Concannon, Ruth M.; Goulding, Susan R.; McCarthy, Cathal M.; Collins, Louise M.; Sullivan, Aideen M.; O'Keeffe, Gerard W.; Science Foundation Ireland; Cure Parkinson's Trust; HORIZON EUROPE Marie Sklodowska-Curie Actions
    Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague–Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.
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    The ups and downs of intermittent hypoxia as a therapy for ventilatory insufficiency
    (John Wiley and Sons Inc, 2022) O'Halloran, Ken D.; Science Foundation Ireland