APC Microbiome Ireland - Journal Articles
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Item 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 ActionsParkinson’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.Item 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 ActionsParkinson’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.Item Diet quality, sleep and quality of life in Parkinson’s disease: a cross-sectional study(Springer, 2022-09-02) Dunk, Danielle; Mulryan, Philip; Affonso, Sean; O'Keeffe, Gerard W.; O'Keeffe, Majella; Sullivan, Aideen M.; Cork Parkinson’s AssociationBackground: Parkinson’s disease (PD) is a neurodegenerative disorder characterised by motor and non-motor symptoms that impact quality of daily life, including diet and sleep. However, relatively little is known about dietary intake and quality in people with PD (PwP). Lifestyle factors, and how they relate to diet, are also insufficiently understood. The aims of this study were to investigate dietary intake and quality, sleep and quality of life in PwP, and to explore the relationships between these factors. Methods: Forty-five community-dwelling participants with PD (n = 45) were recruited to this cross-sectional study through the Cork Parkinson’s Association, Ireland. Dietary intake was assessed using the EPIC food frequency questionnaire, and diet quality was assessed using the Healthy Diet Indicator. Dietary intakes were compared to Irish RDAs for adults > 65 years. Sleep duration and quality were subjectively measured using the PD Sleep Scale and Pittsburgh sleep quality index and objectively measured by actigraphy in a subset of participants (n = 27). QOL was measured using the validated PDQ-39 questionnaire. Results: Energy intake in PwP was significantly higher than that of the general population (2013 vs 1755 kcal/d, p = 0.01), despite their lower mean BMI (25.9 vs 27.7 kg/m2, p = 0.02). Intakes of carbohydrate, protein and fruits and vegetables were significantly higher in PwP compared to recommended and population intakes (all p < 0.01), but fibre intake was significantly lower than recommended (17.3 vs 25 g/d, p ≤ 0.05). Seventy-eight percent of participants had poor dietary quality, and poor sleep quality was associated with poor QOL. Conclusions: Carbohydrates, protein, fruit and vegetable intakes were greater in PwP than population norms, but overall diet quality was low. Interventions to improve dietary and lifestyle factors may improve health and QOL in PwP.Item A combined proteomics and bioinformatics analysis of ZNHIT1-interacting proteins reveals a significant enrichment in proteins associated with mitochondrial function(Elsevier, 2023-05-11) Anantha, Jayanth; Wilson, Fionnuala E.; McCarthy, Erin; Morales-Prieto, Noelia; Mazzocchi, Martina; Collins, Louise M.; Sullivan, Aideen M.; O'Keeffe, Gerard W.; Science Foundation Ireland; Irish Research Council; HORIZON EUROPE Marie Sklodowska-Curie Actions; Cure Parkinson's TrustAdenosine 5'-triphosphate (ATP) is the principal source of cellular energy, which is essential for neuronal health and maintenance. Parkinson’s disease (PD) and other neurodegenerative disorders are characterised by impairments in mitochondrial function and reductions in cellular ATP levels. Thus there is a need to better understand the biology of intracellular regulators of ATP production, in order to inform the development of new neuroprotective therapies for diseases such as PD. One such regulator is Zinc finger HIT-domain containing protein 1 (ZNHIT1). ZNHIT1 is an evolutionarily-conserved component of a chromatin-remodelling complex, which has been recently shown to increase cellular ATP production in SH-SY5Y cells and to protect against impairments in mitochondrial function caused by alpha-synuclein, a protein which is integral to PD pathophysiology. This effect of ZNHIT1 on cellular ATP production is thought to be due to increased expression of genes associated with mitochondrial function, but it is also possible that ZNHIT1 regulates mitochondrial function by binding to mitochondrial proteins. To examine this question, we performed a combined proteomics and bioinformatics analysis to identify ZNHIT1-interacting proteins in SH-SY5Y cells. We report that ZNHIT1-interacting proteins are significantly enriched in multiple functional categories, including mitochondrial transport, ATP synthesis and ATP-dependent activity. Furthermore we also report that the correlation between ZNHIT1 and dopaminergic markers is reduced in the PD brain. These data suggest that the reported beneficial effects of ZNHIT1 on ATP production may be mediated, at least in part, by its direct interaction with mitochondrial proteins and suggest that potential alterations in ZNHIT1 in PD may contribute to the known impairments in ATP generation in midbrain dopaminergic neurons in PD.Item 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 ActionsParkinson'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.