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Research paper on the different cell types Essay

Up-regulation of alpha-synuclein expression and accumulation in cells can lead to alpha-synucleinopathies, that include Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). These 3 diseases affect different cell types. Indeed, oligodendrocytes are severely impaired in MSA patients, whereas cortical neurons are highly lost in LBD. In PD patients, neuromelanin-positive catecholamine neurons in the substantia nigra pars compacta (SN) and locus coeruleus, and norepinephrine and dopaminergic neurons in the enteric nervous system are selectively vulnerable (Sulzer & Surmeier, 2013, Mov Disord). In PD patients, this SN selective vulnerability could be explained by factors enhancing aSyn toxicity, such as dopamine (Conway et al 2001 Science; Mazzulli et al 2007 JBC; Mazzulli et al 2006 J Neurosci; Mosharov et al 2009 Neuron), or neuromelanin, a downstream product of oxidized dopamine (Hirsch, Graybiel, Agid 1988 Nature). The identification of cell-autonomous factors could bring new therapeutic targets for particular synucleinopathies (Wong & Krainc 2017 NatureMedec).

In this perspective, histone deacetylase (HDAC) 6 is a promising therapeutic target for neurodegenerative diseases, and in particular for PD (Van Helleputte et al 2014 ResRepBiol). HDAC6 is enriched in the striatum and SN of a majority of mammals. It mainly deacetylates non-histones substrates, such as α-tubulin, HSP90 and peroxiredoxin ½ proteins. It regulates microtubule-based transport, cell motility, endocytosis, cell migration, autophagy and aggresome formation (Valenzuela-Fernandez et al 2008 Trends Cell Biol). For this reason, HDAC6 has been studied in the context of PD (Su et al., 2011; Du et al., 2010; Olzmann et al., 2007; Lee et al., 2010). The expression of HDAC6 in a Drosophila model of PD would increase aSyn aggregation (Du et al., 2010). Recent studies indicate that HDAC6 mediates the dissociation of heat-shock protein 90 (HSP90) – heat shock factor 1 (Hsf1) – containing complex, and protects dopaminergic neu¬rons against cytotoxic aSyn aggregates by stimulat¬ing aggresome-like inclusion formation. As a consequence, the activation of Hsf1 would lead to the expression of major molecular chaperones to prevent the deleterious effects of aSyn aggregation (Du et al., 2014). These effects still have to be confirmed in other animal models of PD.

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Moreover, the deacetylation effect of HDAC6 in PD needs to be more deeply studied.

Therefore we used a selective inhibitor of HDAC6, Tubastatin A (TubA) in a rat model of PD to investigate the deacetylation state of aSyn in this context and its implication on the protection of the nigrostriatal dopaminergic circuitry.

Because of the imbalance of the HDAC/HAT expression and activity levels, HDAC inhibitors represent tools of interest to modulate HDAC activity and open avenues for PD therapies (Sharma & Taliyan, 2015). Although, the precise molecular mechanisms underlying these effects are still unclear and demand further attention.

Post-translational modifications (PTM) have emerged as important determinants of physiological and pathological functions of aSyn in vitro and in vivo. Indeed, thanks to biochemical analysis of LB from PD patients brain, numerous PTMs in aSyn have been described (Oueslati et al., 2010), such as ubiquitination (Nonaka et al., 2005), sumoylation (Krumova et al., 2011), phosphorylation (Anderson et al., 2006; Paleologou et al., 2010; Cavallarin et al., 2010), truncation (Li et al., 2005; Liu et al., 2005), oxidation (Zhou et al., 2010), and N-terminal acetylation (Anderson et al., 2006; Ohrfelt et al., 2010).

Some of these PTMs have been linked to pathogenic processes (Oueslati et al., 2009; Cavallarin et al., 2010), as they might induce aSyn conformational changes and affect oligomerization (Zarbiv et al., 2014).

Lysine acetylation has been shown to co-regulates major cellular functions such as chromatin remodeling, cell-cycle, actin nucleation (Choudhary et al 2009 Science). However, due to its reversibility nature, the possible modulating of aSyn structure, function, aggregation, and cytotoxicity by lysine acetylation is still unknown.

The present study investigated the potential effect of TubA in a cell model and in a rat model of PD and dissected the potential molecular mechanisms underlying this effect.

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