## 5 Discussion
All these results support the notion that the _HSPA1A_ gene is under strong selection and that its functions must be conserved [149], which would explain why no patients with pathogenic mutations of this gene have been found. The Hsp90 (HSPC) family, including five members and various isoforms expressed in specific cellular organelles, is highly conserved from early eukaryotes to humans and plays important roles in protein homeostasis (references in [21]). Hsp90 chaperones have a wide array of client proteins and, together with their co-chaperones and co-factors, participate in cell survival, cell-cycle control mechanisms, hormone signaling and other signaling pathways, and apoptosis [150]. In addition, Hsp90 has been implicated in the pathogenesis of Alzheimer's disease and Parkinson's disease [151,152]. However, it is noteworthy that no Hsp90 mutations have been described yet as an etiological-pathogenic factor in NCPs. The same message is given by analysis of Hsp90 genetic polymorphisms. Polymorphic variants in introns and exons of the human Hsp90 beta (_HSPC3_) gene have been detected with no apparent effects on phenotype [153]. In recent years, along with genetic NCPs, attention has also been directed to acquired NCPs associated with molecular chaperones with PTMs. For instance, in vivo studies demonstrated that changes in the AMPylation balance of molecular chaperones could influence cell fate in physiological [125] and pathological conditions, such as PD and AD [127]. Human FICD AMPJates various amino acids in the Hsp70, DNAJB1, and Hsp90 chaperones. AMPylation levels regulate the correct neurogenesis and neuronal conduction [123,126]. So far there are no data suggesting that chaperone AMPylation may be disruptive and contribute to the pathogenic mechanism of neurological disorders. Nitration of Hsp90 (HSPC) family members in relation to ALS disease is an example of the differential outcomes one can expect depending on the site and level of the PTM. Furthermore, considering the importance of mitochondrial activity in neuronal cells, one may assume that nitrated Hsp90 may be associated with acquired NCPs in addition to those for ALS. Acquired NCPs could be the result of PTMs in molecular chaperones and of PTMs in co-chaperones, chaperone co-factors or chaperone interactors, as illustrated by the consequences of phosphorylation of Hsp90/Cdc37 complex [133,135]. Two coexisting PTMs, phosphorylation and acetylation, in the VCP in the nucleus may promote histone deacetylation [138]. VCP could also undergo methylation and S-glutathionylation, two modifications that occur during oxidative stress with impairment of ATPase activity [139]. Since oxidative stress is a prevalent feature of neurodegenerative diseases, it is possible that modified VCP also plays a pathogenic role in NCPs. Pathogenic chaperones with aberrant PTMs associated with NCPs, other than those described above, have not been reported. Most of the naturally occurring or induced PTMs in Hsp60 (HSPD1) with a pathogenic role have been implicated in carcinogenesis [154,155,156,157],apoptosis signaling regulation [158; 159], and immune system regulation [160], but none has been associated with NCPs [25; 161]. However, an involvement of Hsp60 (HSPD1) in AD and PD is under scrutiny. It is possible that Hsp60 with aberrant PTMs and/or with abnormal levels and location, i.e., intra- or extracellular, and when intracellular intra- or extramitochondrial, may be pathogenic in neurological disorders [25]. The number of multiple PTMs that can occur on a molecular chaperone is strikingly high, e.g., 60% and 56% of the T, Y, and S residues of Hsp70 (HSPA8) and Hsp90, respectively, could be phosphorylated [123] (Figure 3). In addition, the same residue could be subjected to different PTMs, and several PTMs can also occur on the relevant co-chaperones and collaborators.