## 5 Discussion  
In the last few years, an increasing number of scientific reports have highlighted the involvement of members of the CS in the pathogenesis of diverse neurological disorders. It was found that genetic and/or acquired malfunction (or lack of function) of members of the CS are implicated in the pathogenic mechanisms underlying NCPs (Figure 2). The heterogeneity of these disorders and the difficulties implied in the study of the nervous system in humans are the major challenges for physicians and other investigators willing to elucidate the relevant molecular mechanisms and to develop efficacious treatment strategies. The data reported thus far, some of which has been briefly discussed in the previous sections, indicate that pathogenic variants of members of the sHsp, DnaJ(Hsp40), and CCT families, and of the Hsp60 gene, tend to cause predominantly motor disorders, although sensory and mental functions may also be affected [24; 28; 32; 33; 36; 46; 49; 52; 54]. For example, a missense mutation of the subunit number 5 of CCT, CCT5, was reported to be accompanied by a phenotype characterized mostly by distal sensory mutilating neuropathy [56; 57]. In contrast, another recently discovered mutant located in a different structural domain of CCT5 was associated with a motor distal neuropathy without mutilation [58]. Thus, the impact of the mutation on the properties and functions of the chaperone molecule, and the accompanying tissue abnormalities and lesions observed in patients may greatly differ, depending on the location of the mutant amino acid, but other elements, e.g., environmental and nutritional factors that may also contribute to the generation of diverse phenotypes cannot be excluded. Other genetic NCPs discussed are caused by variants of a subfamily of CCT genes composed of the BBS6 (MKKS), BBS10, and BBS12 genes [24; 59; 60; 61; 63; 64; 65]. Cognitive deficit was recorded only in patients with pathogenic variants of the CCT5 (the newly reported mutation p.(Leu224 Val)), _DNAJ_C, and _BBS_ genes (Figure 2). Only one of the members of the Hsp70(DnaK) family, the mitochondrial Hsp70 (mtHsp70 also named mortalin or HSPA9) has been reported with pathogenic mutations causing a syndrome that can be classified as NCP. Other members of this family, such  
Figure 2: Molecular chaperones involved in genetic neurochaperonopathies (NCPs). Various molecular chaperones are involved in genetic NCPs, but only some (orange) are associated with cognitive impairment, while others (blue) are not. as the HSPA1A and HSPA1B, whose genes are organized in tandem within the so called _HSPA1_-cluster [140] are stress-inducible and have been implicated in the pathogenesis of several diseases, such as cancer and neurodegenerative conditions, but their genes were normal [141,142]. This pathogenicity of the Hsp70 molecules fits the description of acquired chaperopathies by mistake or collaborationism, in which apparently normal chaperones help the disease rather than protect from it. The lack of genetic NCPs associated with mutations in _HSPA1A_ and _HSPA1B_ genes could be related to their vital roles suggested also by their evolutionary conservation [95]. This is also suggested by the fact that the majority of polymorphisms identified in the human _HSPA1_-cluster are in the UTR regions, and the most common SNPs occurring in the coding regions are synonymous and thus, do not affect the proteins' amino acid sequences [143,144]. A few studies experimentally investigated the impact of human _HSPA1A_-_1B_ mutations on the function/expression of the encoded proteins [145,146,147,148]. The functional analysis of six naturally occurring variants of the _HSPA1A_ gene revealed that these variants result in significant functional alterations, affecting ATP-hydrolysis rate and substrate-binding ability, likely by altering the allosteric communication between its two major domains. However, they are rare mutations, with very low penetrance in the human population.