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    Conflict of interest statement
    Transparency document
    Introduction As our CCK-8 structure ages, neurodegenerative diseases have become a pressing problem [1,2]. These disorders are incurable, relentless and often fatal shortly after diagnosis [[2], [3], [4]]. While these ailments vary in their specific pathophysiology and clinical presentation, they share several puzzling features. For instance, despite intense genetic analysis of large patient populations, a significant proportion of neurodegenerative disease cases have no known genetic basis [5]. Furthermore, several of these disorders show proteinaceous inclusions comprised of misfolded proteins [6]. Throughout the years, various medications and therapies have been considered for these diseases, many resulting in less than satisfactory results [7]. Hence, the need for novel treatments able to ameliorate symptoms and stop disease progress is at an all-time high.
    Histone modifications in neurodegenerative disease
    Histone modifications in neurodegenerative disease: New avenues for treatment HDAC inhibitors have been studied for potential use as therapies for ALS and FTD. [25] At present, butyrates are the most commonly studied class of HDAC inhibitors in humans, as they are able to easily penetrate the blood-brain barrier [144]. Sodium phenylbutyrate inhibits most HDACs, except for class III HDACs and class II HDAC6 and HDAC10 [145]. In ALS mice models, treatment with sodium phenylbutyrate enhanced overall histone acetylation and improved survival rates [144]. Remarkably, in humans, sodium phenylbutyrate was not only safe and tolerable, but it was also able to increase histone acetylation in blood buffy-coat specimens while decreasing ALS symptoms [146]. Treatment of SOD1 G93A transgenic ALS mice with both riluzole and sodium phenylbutyrate increased H4 acetylation and survival by 21.5%, more than either riluzole or sodium phenylbutyrate on their own [147]. In the case of PD, administration of HDAC inhibitors in vivo or in vitro rescued α‑synuclein-induced toxicity [148]. Despite their name, it is important to note that HDACs act upon several other non-histone targets [149,150]. Therefore, there are other possible cellular mechanisms involving acetylation – independent of histones – by which HDAC inhibition can lead to reduction of toxicity. Nevertheless, combination of traditional treatments and treatments targeting epigenetic mechanisms might be in the not so distant future for ALS treatment. In FRDA, treatment with nicotinamide (vitamin B3), an HDAC inhibitor, resulted in upregulation of the FXN gene by way of decreasing H3K9me3 and H3K27me3 at the FXN gene, and consequently increasing histone acetylation in both H3 and H4 [151]. This reveals a possible treatment for FRDA, especially when considering the widespread availability, tolerability and affordability of vitamin B3. In the case of SCA1 however, treatment with HDAC inhibitors may be inadequate. ATXN1 is the protein believed to be responsible for SCA1, and has been found to bind HDAC3 causing transcriptional repression in vitro [152], however depletion of HDAC3 does not change the SCA1 phenotype. Indeed, HDAC3 depletion did not decrease neurodegeneration in SCA1 transgenic mice, suggesting that HDAC inhibitors may not be a viable course of treatment [153].
    Concluding remarks
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    Acknowledgments Brooklyn College and an NIH NINDS Advanced Postdoctoral Career Transition Award (K22NS09131401) supported M.P.T. S.N.C. was supported by The Graduate Center of the City University of New York.
    Introduction Parkinson's disease (PD) is the second most common neurodegenerative disorder in the United States, characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of protein aggregates known as Lewy bodies [1]. The primary components of Lewy bodies are α-synuclein and, often, leucine-rich repeat kinase 2 (LRRK2), whose genetic mutations have been historically implicated in cases of autosomal dominant PD [2,3]. There are various genetic factors contributing to the pathogenesis of PD, but only mutations in α-synuclein and LRRK2 cause clinical and neuropathological phenotypes closely resembling the sporadic cases [3].