Alterazioni nel nucleo soprachiasmatico nella sclerosi laterale amiotrofica

The Amyotrophic Lateral Sclerosis (ALS) is an adult neurodegenerative disease, with a medial survival around 2-4 years from onset. Exist two different types of ALS, a familiar type (fALS) and a sporadic type (sALS). The main symptom of ALS is the motor neuron degeneration, this condition is the most common cause of death for ALS patients: the respiratory muscles atrophy. There are many genetic mutations associated with the development of the Amyotrophic Lateral Sclerosis, the most common are: C9ORF72; SOD1; TARDBP; FUS. The mutation of p62 can be itself a cause of the ALS development, p62 is a molecule involved in the autophagic process and in the degradation of misfolded proteins or damaged substrates. These gene mutations induce an impairment of many cellular processes, like the nucleocytoplasmic transport and the axonal and vesicular transport, leading to the development of a condition of neuroinflammation in the motor neurons causing the loss of muscle innervation. Associated with the motor symptoms there are the cognitive symptoms, the most common among ALS patients are metabolic dysfunction and sleep-wake cycle disturbances. The hypothalamus is the brain areas responsible for the control of the metabolic process and the circadian rhythm, more in details the Paraventricular nucleus (PVN) and the Suprachiasmatic Nucleus (SCN) are the hypothalamic nuclei involved in these processes’ regulation. In previous research was demonstrate the PVN impairment in the ALS patients, the aim of this research is to demonstrate damage also at SCN level. In order to do so twelve ALS patients were analyzed and compared with a group of control subjects (match for age, sex, postmortem delay and cause of death). The tissues were stained with two different antibodies, against arginine vasopressin and vasoactive intestinal peptide, these are the main molecules produced from the SCN. Other two antibodies were used to define the presence of aggregates in the SCN (anti-pTDP-43) and to demonstrate the SCN impairment (anti-p62). The results showed a significant difference between ALS and control groups in the level of p62OD and a positive correlation between the p62OD values and the VIP total counted cells. The immunostaining results for VIP and AVP neurons in the SCN shows a significant difference only in VIP counted neurons, not for the AVP and the correlation between the AVP/VIP total number of cells with the clock time of death, revealed a non-regular distribution of the values in the ALS patients, respect to the control group. All these results demonstrate an impairment of the hypothalamic SCN of ALS patients, this is a starting point for new therapies development for this disease in order to give to the patients a better quality of life. Further studies are needed to better understand which mutated proteins are responsible of the p62 aggregation.