## 3 Genetic NCPs
### The Chaperonins  
The best-known examples of genetic neurochaperonopathies are those involving members belonging to the family of chaperonins, including the group I chaperonin Hsp60 (HSPD1, of which a few pathogenic variants have been identified in humans) and the group II chaperonin CCT. **Chaperonins of Group I. ** The chaperonin HSPD1 is typically expressed within the mitochondrion where it assists the folding of proteins destined to the matrix together with the co-chaperonin Hsp10 (HSPE1) (HSP10; [97; 45; 96]). HSPD1 plays a key role not only in the maintenance of protein homeostasis in mitochondria, but also in sustaining cellular viability, since complete loss of the protein impaired mammalian development and postnatal survival, as demonstrated by an in vivo model of mice homozygous for an inactivation of _HSPD1_ gene [98]. In humans, missense mutations of the _HSPD1_ gene have been found associated with severe and chronic nervous system diseases. These include: 1) a dominantly inherited form of Spastic Paraplegia (SPG13) affecting motor neurons with the longest axons in the spinal cord and caused by either one of two missense mutations occurring at different positions, i.e., p.(Val98 Ile) and p.(Gln461 Glu), [54; 55; 99] (Table 1); and 2) a recessively inherited hypo-myelinating leukodystrophy (HLD4), also known as MitCHAP60 disease, which is a fatal early-onset neurodegenerative disorder characterized by pronounced cerebral hypomyelination and is caused by a single specific missense mutation, i.e., p.(Asp29 Gly) [52; 53] (Table 1). In vitro and in vivo studies have shown that these mutations destabilized the chaperonin oligomeric complex and reduced its ATPase and folding activities compared to the wild type form [100; 101]. In addition to these two well-known neurological conditions, many others of various degrees of severity may be caused by other _HSPD1_ mutations that are known to occur in human genomes [97; 102]. A point missense mutation, p.(Leu73 Phe), in the gene encoding the co-chaperonin Hsp10 or HSPE1 (_lsp10_ or _HSPE1_ gene), has been found in a patient with a history of infantile spasms, hypotonia, developmental delay, a slightly enlarged liver, macrocephaly, and mild non-specific dysmorphic features [45] (Table 1). The association between neurological disorders and _HSPD1/E1_ genes mutations is related to the great sensitivity of neuronal cells to mitochondrial dysfunction, since they have a metabolism mainly based on oxidative phosphorylation [103]. In vitro studies have shown that the expression of HSPD1 variants alters mitochondrial morphology, dynamics, and functionality [104; 105]. **Chaperonins of Group II. ** This group includes the CCT family, which in humans is composed of nine subunits: 1 through 8, with two versions of subunit 6; plus, three chaperones named BBS6, BBS10, and BBS12, which are involved in cilia biogenesis; and two other evolutionarily related molecules, CCT8L1 and CCT8L2, of which little is known [106] (Figure 1). Figure 1: Evolutionary trees of chaperonin-containing TCP-1 (CCT) chaperonins. (**Left**): Maximum-likelihood tree of human chaperonins, including CCT monomers, MKKS, BBS10, and BBS12 as well as the members of the CCT8L class, CCT8L1 and CCT8L2. Numbers associated with each branch indicate bootstrap support from 100 replicates. Tree rooted by the archaeal thermosome \(\alpha\) subunit of _Sulfolous solitatricus_ (Ss_ThAs). (**Right**): Bayesian tree of the same sequences. The numbers assigned to each branch indicate posterior probabilities. Tree rooted by the thermosome \(\alpha\) subunit of _Thermoplasma acidophilum_ (Ta_ThAs). Scale bars, number of substitutions per position for a unit branch length. Reproduced from Reference [106]  
Here, we will consider chaperonopathies of the subunit CCT5 and those of the BBS cluster. BBS stands for Bardet-Biedl syndrome, which is the pathological condition caused by abnormalities in any one of these three chaperones.