## 3 Genetic NCPs
### DnaJ(Hsp40)  
Mutations in members of the Hsp40(DnaJ) family have been associated with neurologic and muscular disorders. Two examples are variants of the _DNJAB2_ and _DNAJC5_ genes, encoding members of the subfamilies B and C, respectively. _DNAJB2_ is mainly expressed in neurons and plays anti-protein aggregation and neuroprotective roles, as shown in models of neurodegenerative disorders [87; 88; 89]. The mutation c.352+1G-A in _DNAJB2_ was found associated with autosomal recessive distal spinal muscular atrophy-5 (DSMA5), a type of dHMN with young adult onset and characterized by progressive distal muscle weakness and atrophy with gait impairment and loss of reflexes [47] (Table 1). This genetic variant reduced or abolished chaperone expression, with a consequent accumulation and aggregation of misfolded proteins, which would cause lower motor neurons degeneration [47]. The same _DNAJB2_ variant was found in patients diagnosed with CMT2, and careful examination of phenotype and clinical evolution showed that pure motor impairment occurred early in the disease course, with no initial sensory symptoms, but sensory disturbances in the lower limbs appeared as the disease progressed [90]. Two other _DNAJB2_ gene variants were found in two families (Table 1). One (c.229+1G-A) showed a dHMN phenotype, with signs of distal muscular atrophy and paresis; the other, causing the missense mutation p.(Tyr5 Cys), showed a CMT2 phenotype, with a noticeable sensory involvement, extending the group of _DNAJB2_-related diseases to include sensory neuropathy [46]. However, another evaluation of the phenotypes associated with these two latter genetic variations has classified them as DSMA5 (for details see the corresponding page on ClinVar database).  
DNAJC5, also known as cysteine string protein (CSP), is abundant in neuronal cells and is a key element of the synaptic molecular machinery [48]. Two different genetic variations, an amino acid deletion and an amino acid substitution, were found associated with autosomal dominant adult-onset neuronal ceroid lipofuscinosi-4B (CLN4B), also known as [PERSON] disease [49; 50; 51; 52]. These mutations affect two evolutionarily conserved leucine residues located in a conserved region of the cysteine-string domain that is involved in palmitoylation and membrane targeting of the protein [91]. CLN4B belongs to the group of neuronal ceroid lipofuscinosis (NCLs), a genetically heterogeneous group of at least nine neurodegenerative disorders, clinically characterized by progressive cognitive and motor impairment, visual impairment, epileptic seizures, and premature death. Despite the different ages of onset, all forms presented a common feature, i.e., the lysosomal accumulation of auto-fluorescent lipo-pigment in neuronal cells and peripheral tissues, which caused progressive and selective neurodegeneration and gliosis with secondary white matter lesions [92; 93]. To clarify the molecular mechanisms responsible for the negative effects of the identified CSP mutations in neuronal cells, functional in vitro studies were performed. It was shown that both mutants had an abnormal intracellular localization and were less efficiently palmitylated compared to the wild type protein. Moreover, they formed aggregates, causing CSP depletion that, in turn, could be responsible for the inhibition of synapse formation and synaptic transmission [49; 94].