Abstract
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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder that is characterised by progressive loss of midbrain dopaminergic neurons from the substantia nigra (SN) [1, 2]
We enriched this gene list for those most likely to be expressed in dopaminergic neurons by comparing the n = 303 list to those genes that were co-expressed with two dopaminergic markers, TH and ALDH1A1, in the SN
We performed a gene set enrichment analysis using STRING and found a significant enrichment of genes associated with the histone deacetylase complex (GO:0,000,118); these were zinc finger HIT-type containing 1 (ZNHIT1), HDAC5, HDAC6, SAP18 and MORF4L1 (Fig. 1D)
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder that is characterised by progressive loss of midbrain dopaminergic neurons from the substantia nigra (SN) [1, 2] The axons of these neurons form the nigrostriatal pathway, which innervates the striatum and is a key part of the basal ganglia circuitry which regulates voluntary movement [1, 2]. Several studies have shown nigrostriatal degeneration in rodents and non-human primates, resulting from injection of α-Syn pre-formed fibrils (PFFs) or recombinant adeno-associated virus vector (rAAV)-mediated α-Syn overexpression (for review see [20]) These data show that α-Syn accumulation plays a role in dopaminergic degeneration in PD. It is important to investigate the genes and molecular networks that are affected by α-Syn, in order to elucidate the molecular basis of cellular dysfunction in PD and to identify new therapeutic targets
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