Infantile-onset Ascending Hereditary Spastic Paralysis, Juvenile Primary Lateral Sclerosis and Juvenile Amyotrophic Lateral Sclerosis are all motor neuron diseases related to mutations on the ALS2 gene, encoding for a 1657 amino acids protein named Alsin. This ~185 kDa multi-domain protein is ubiquitously expressed in various human tissues, mostly in the brain and the spinal cord. Several investigations have indicated how mutations within Alsin’s structured domains may be responsible for the alteration of Alsin’s native oligomerization state or Alsin’s propensity to interact with protein partners. In this review paper, we propose a description of differences and similarities characterizing the above-mentioned ALS2-related rare neurodegenerative disorders, pointing attention to the effects of ALS2 mutation from molecule to organ and at the system level. Known cases were collected through a literature review and rationalized to deeply elucidate the neurodegenerative clinical outcomes as consequences of ALS2 mutations.

The identification of the mechanisms underlying the transfer of mechanical vibrations in protein complexes is crucial to understand how these super-assemblies are stabilized to perform specific functions within the cell. In this context, the study of the structural communication and the propagation of mechanical stimuli within the microtubule (MT) is important given the pivotal role of the latter in cell viability. In this study, we employed molecular modelling and the dynamical network analysis approaches to analyse the MT. The results highlight that $$\beta$$β -tubulin drives the transfer of mechanical information between protofilaments (PFs), which is altered at the seam due to a different interaction pattern. Moreover, while the key residues involved in the structural communication along the PF are generally conserved, a higher diversity was observed for amino acids mediating the lateral communication. Taken together, these results might explain why MTs with different PF numbers are formed in different organisms or with different $$\beta$$β -tubulin isotypes.

Understanding the intricate interplay between structural features and signal-processing events is crucial for unravelling the mechanisms of biomolecular systems. G protein-coupled receptors (GPCRs), a pervasive protein family in humans, serve a wide spectrum of vital functions. TAS2Rs, a subfamily of GPCRs, play a primary role in recognizing bitter molecules and triggering events leading to the perception of bitterness, a crucial defence mechanism against spoiled or poisonous food. Beyond taste, TAS2Rs function is associated with many diseases as they are expressed in several extra-oral tissues. Since the precise mechanism of TAS2R activation is poorly understood, this work aims to characterize the mechanisms underlying the signal transduction on the recently experimentally solved human TAS2R46 bitter taste receptor using molecular dynamics simulations coupled with network-based analysis. The results show that the allosteric activation of the receptor is associated with more correlated dynamics of the receptor and the formation of an interaction between two helices which mainly convey the signal transferring from the extracellular to the intracellular region. By elucidating the hallmarks of the allosteric network of TAS2R46 under varying conditions (ligand-bound, ligand-free, and transition states), this study has enabled the identification of the unique functional mechanisms of this receptor, thereby establishing a foundation for a more profound characterisation of this intriguing class of receptors. Highlights: The dynamics of TAS2R46 in different states were studied through molecular dynamics and network analysis. The presence of the bitter agonist increases intra-protein correlations. TM3 and TM6 helices mediate the allosteric network in Holo TAS2R46. The rotation of Y241 ^6.48 residue is pivotal in the allosteric network for the Holo TAS2R46.

The Infantile-onset Ascending Hereditary Spastic Paralysis (IAHSP) is an incurable rare neurodegerative disease related to a mutation-driven aberrant behaviour of the Alsin protein. The lack of information on Alsin atomic structure limits a complete understanding on pathology mechanisms. In this work, molecular modelling techniques have been applied to shed lights on Alsin folding dynamics and misfunction induced by aberrant mutations.