Molecular chaperones rang at the top of the therapeutic strategies concepts. Molecular chaperones play a key role in maintaining cellular proteostasis by facilitating the correct folding of cellular proteins to guarantee their function or by advancing the degradation of terminally misfolded proteins to prevent damage. With advancing age, the capability of this proteostasis supporting network tends to weaken, which facilitates the progression of neurodegenerative diseases. In general, two key hypotheses exist explaining for polyQ expansions may trigger cellular dysfunction: (i) neurotoxicity stems from the ability of polyQexpanded proteins to recruit other vital cellular proteins into the aggregates; (ii) aggregating polyQ proteins partly inhibit the ubiquitin-proteasome system for protein degradation. These two models are not exclusive but may act in concert. Overall, protein misfolding and aggregation are prevented by the machinery of molecular chaperones. Some chaperones such as the Hsp70 family members also modify polyQ aggregation and inhibit its toxicity. These results point out the functional relationship between molecular chaperones, the ubiquitin-proteasome system, and polyQ aggregation. Chaperone therapy is a recently developed therapeutic strategy against protein misfolding diseases. Molecular chaperones utilizing the heat shock protein and other chaperone proteins have been reported able to handle abnormally accumulated proteins as a new approach to neurodegenerative diseases. Understanding how chaperones interrelate to disease progression is essential for the advancement of therapeutic strategies to combat these debilitating diseases. Disease models constitute another widely explored concept in the polyQ diseaserelated documents in the CAS Content Collection (Figure ). PolyQ diseases affect neural tissue, which is particularly hard to obtain from patients. Therefore, cellular and organism models are essential for successful research in this area. Cellular models are indispensable element in research and have significant contributions to the discovery and validation of multiple pathological changes related to polyQ diseases. A variety of cellular models include (i) fibroblasts extracted from patients by a skin biopsy ; (ii) embryonic stem cells, which contain disease-associated genetic patterns and can be further differentiated into any cell in the human body 190 ; (iii) induced pluripotent stem cells comprising patient-specific genetic information, dividing unlimitedly and able to be differentiated into any disease-related cell populations, including neurons ; (iv) human embryonic kidney 293 (HEK 293T) cells having the advantage of simple transfection and high-level transgene expression ; and (v) yeast cell models, inexpensive and appropriate for large-scale genetic and pharmacological screening. Further, animal models exhibiting more advanced phenotypes and typical behaviors are an essential requisite for polyQ disease modeling. Simple model organisms include the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the zebrafish Danio rerio. They helped verify pathogenic features of polyQ diseases such as the aggregate formation, the mutant proteins toxicity, the neurotransmission deficiencies and the progressive neuronal degeneration. Rodent models have been successfully used in studying behavioral phenotypes of Huntington's disease. Recently, large mammalian models of Huntington's disease and SCA3 in monkeys, marmosets, minipigs, pigs, and sheep have been generated by using genome-editing technology. The advancement of modern gene-editing technologies, such as meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and especially the CRISPR-Cas9 technique, has a particular value for the generation of relevant polyQ models, which have substantially advanced the research process. Stem cells are also a commonly explored concept in the polyQ disease-associated documents in the CAS Content Collection (Figure ). One of the novel therapeutic approaches for treating polyQ diseases focuses on the development of cell replacement therapies. Such therapies are anticipated in either replacing damaged neurons or stimulating the endogenous neurogenesis pathways of the brain. Stem cells represent a favorable tool for regenerative medicine in human disorders cure. Successful stem-cell transplantation attempts in models of polyQ diseases have been made and believed to hold great promise for the advancement of new cell-based therapies for polyQ diseases. Histone deacetylase (HADC) enzymes are known to remove acetyl group from lysine residue of histones and other proteins. In neurodegenerative diseases, histone acetylation homeostasis is significantly compromised, giving rise to hypoacetylation. In particular, it has been evidenced that the chromatin acetylation status is critically impaired in polyQ disorders. Therefore, histone hyperacetylation triggered by inhibition of HDACs has neuroprotective effect and HDAC inhibitors have been suggested as a relevant treatment approach. Small molecule inhibitors of HDACs notably affect neuronal differentiation and neurite outgrowth, and thus exhibit a potential as therapeutic agents for treatment of neurodegenerative diseases including polyQ diseases. These inhibitors of the zinc-dependent classes of HDACs belong to 4 classes regarding their chemical structure: hydroxamates, cyclic peptides, short chain fatty acids and benzamides. The clinical application of these broadly acting compounds for neurodegenerative disorders is limited however by their toxicity. Moreover, additional studies are needed to fully understand the mechanisms associated with the beneficial effects of selective HDAC inhibitors, to identify specific substrates and to further define the pathways in which specific HDAC enzymes are involved.