Distal hereditary motor neuropathies (dHMNs) are clinically and genetically heterogeneous neurological conditions characterized by degeneration of the lower motor neurons. So far, 18 dHMN genes have been identified, however, about 80% of dHMN cases remain without a molecular diagnosis. By a combination of autozygosity mapping, identity-by-descent segment detection and whole-exome sequencing approaches, we identified two novel homozygous mutations in the SIGMAR1 gene (p.E138Q and p.E150K) in two distinct Italian families affected by an autosomal recessive form of HMN. Functional analyses in several neuronal cell lines strongly support the pathogenicity of the mutations and provide insights into the underlying pathomechanisms involving the regulation of ER-mitochondria tethering, Cahomeostasis and autophagy. Indeed, in vitro, both mutations reduce cell viability, the formation of abnormal protein aggregates preventing the correct targeting of sigma-1R protein to the mitochondria-associated ER membrane (MAM) and thus impinging on the global Casignalling. Our data definitively demonstrate the involvement of SIGMAR1 in motor neuron maintenance and survival by correlating, for the first time in the Caucasian population, mutations in this gene to distal motor dysfunction and highlight the chaperone activity of sigma-1R at the MAM as a critical aspect in dHMN pathology.

Metals can directly or indirectly cause an increase in reactive oxygen species (ROS) accumulation in cells, and this may result in programmed cell death. A number of previous studies have shown that zinc (Zn) modulates mitogenic activity via several signalling pathways, such as AKT, mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF -κB), AP-1 and p53. The exact role that Zn plays in the regulation of apoptosis remains ambiguous. Intracellular free Zn modulates p53 activity and stability, and excess Zn alters the p53 protein structure and down-regulates p53's binding to DNA. Copper (Cu) accumulation causes apoptosis that seems to be mediated by DNA damage and subsequent p53 activation. Cu can also displace Zn from its normal binding site on p53, resulting in abnormal protein folding and disruption of p53 function. In spite of the induction of the tumour suppressor p53, hepatic Cu accumulation significantly increases the risk of cancerous neoplasm both in humans and rats, suggesting that p53 function may be impaired in these cells. It is generally understood that imbalances in Cu and Zn levels may lead to a higher prevalence of p53 mutations. An increased number of p53 mutations have been found in liver samples from Wilson's disease (WD) patients. High levels of the p53 mutation most probably contribute to the pathogenesis of cancer in individuals with WD, but the cause and effect are not clear. The protein p53 also plays a crucial role in the transcriptional regulation of metallothionein, which indicates a novel regulatory role for p53. This review discusses the central role of p53 and the redox-inert metal Zn in the cellular stress responses induced by the redox active biometal Cu.

It has become more and more evident that the BCL-2 family proteins mediate a wide range of non-apoptotic functions. The pro-apoptotic BAX protein has been reported in interphasic nuclei. Whether the nuclear form of BAX could be involved in non-apoptotic function is still unknown. Our study showed for the first time that BAX was associated with chromatin in vitro. Next, we used gain and loss of function approaches to decipher the potential role of nuclear BAX in non-apoptotic cells. In vitro, nuclear BAX promoted cell proliferation in lung epithelial cells and primary human lung fibroblasts by modulating CDKN1A expression. Interestingly, BAX occupancy of CDKN1A promoter was specifically enriched close to the transcription-starting site. Nuclear BAX also modulated the basal myofibroblastic differentiation and migration of primary human lung fibroblasts. Finally, BAX nuclear localization was associated in vivo with the remodelling of lung parenchyma during development, tumorigenesis as well as fibrosis compared to control adult human lungs. Hence, our study established for the first time, a strong link between the nuclear localization of the pro-apoptotic BAX protein and key basic cellular functions in the non-apoptotic setting.