Complexity of Generating Mouse Models to Study the Upper Motor Neurons: Let Us Shift Focus from Mice to Neurons

Motor neuron circuitry is one of the most elaborate circuitries in our body, which ensures voluntary and skilled movement that requires cognitive input. Therefore, both the cortex and the spinal cord are involved. The cortex has special importance for motor neuron diseases, in which initiation and modulation of voluntary movement is affected. Amyotrophic lateral sclerosis (ALS) is defined by the progressive degeneration of both the upper and lower motor neurons, whereas hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are characterized mainly by the loss of upper motor neurons. In an effort to reveal the cellular and molecular basis of neuronal degeneration, numerous model systems are generated, and mouse models are no exception. However, there are many different levels of complexities that need to be considered when developing mouse models. Here, we focus our attention to the upper motor neurons, which are one of the most challenging neuron populations to study. Since mice and human differ greatly at a species level, but the cells/neurons in mice and human share many common aspects of cell biology, we offer a solution by focusing our attention to the affected neurons to reveal the complexities of diseases at a cellular level and to improve translational efforts

Mutations and Protein Interaction Landscape Reveal Key Cellular Events Perturbed in Upper Motor Neurons with HSP and PLS

Hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are rare motor neuron diseases, which affect mostly the upper motor neurons (UMNs) in patients. The UMNs display early vulnerability and progressive degeneration, while other cortical neurons mostly remain functional. Identification of numerous mutations either directly linked or associated with HSP and PLS begins to reveal the genetic component of UMN diseases. Since each of these mutations are identified on genes that code for a protein, and because cellular functions mostly depend on protein-protein interactions, we hypothesized that the mutations detected in patients and the alterations in protein interaction domains would hold the key to unravel the underlying causes of their vulnerability. In an effort to bring a mechanistic insight, we utilized computational analyses to identify interaction partners of proteins and developed the protein-protein interaction landscape with respect to HSP and PLS. Protein-protein interaction domains, upstream regulators and canonical pathways begin to highlight key cellular events. Here we report that proteins involved in maintaining lipid homeostasis and cytoarchitectural dynamics and their interactions are of great importance for UMN health and stability. Their perturbation may result in neuronal vulnerability, and thus maintaining their balance could offer therapeutic interventions

2-Year-Old and 3-Year-Old Italian ALS Patients with Novel ALS2 Mutations: Identification of Key Metabolites in Their Serum and Plasma

Pathogenic variants in ALS2 have been detected mostly in juvenile cases of amyotrophic lateral sclerosis (ALS), affecting mainly children and teenagers. Patients with ALS2 mutations demonstrate early onset cortical involvement in ALS. Currently, there are no effective treatment options. There is an immense need to reveal the underlying causes of the disease and to identify potential biomarkers. To shed light onto the metabolomic events that are perturbed with respect to ALS2 mutations, we investigated the metabolites present in the serum and plasma of a three-year-old female patient (AO) harboring pathogenic variants in ALS2, together with her relatives, healthy male and female controls, as well as another two-year-old patient DH, who had mutations at different locations and domains of ALS2. Serum and plasma samples were analyzed with a quantitative metabolomic approach to reveal the identity of metabolites present in serum and plasma. This study not only shed light onto the perturbed cellular pathways, but also began to reveal the presence of a distinct set of key metabolites that are selectively present or absent with respect to ALS2 mutations, laying the foundation for utilizing metabolites as potential biomarkers for a subset of ALS