Form Of Juvenile Amyotrophic Lateral Sclerosis Research Articles

Case report:Juvenile Amyotrophic lateral sclerosis: classical wine glass sign on MRI

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is a chronic degenerative neurologic disease and is characterized by the selective involvement of the motor system. Usually patients present with upper motor neuron (UMN) and lower motor neuron (LMN) compromise. Degeneration of the UMN in the cerebral cortex is one of the main pathologic changes in ALS. These changes usually affects corticospinal tracts (CST) leading to degeneration of the fibres which show characteristic hyper intensities along the tracts leading to the “wine glass sign”. Patients with ALS usually present in the 6th decade of life; presentation in pediatric age in the form of juvenile ALS (JALS) being rare.

Case report:Juvenile Amyotrophic lateral sclerosis: classical wine glass sign on MRI

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is a chronic degenerative neurologic disease and is characterized by the selective involvement of the motor system. Usually patients present with upper motor neuron (UMN) and lower motor neuron (LMN) compromise. Degeneration of the UMN in the cerebral cortex is one of the main pathologic changes in ALS. These changes usually affects corticospinal tracts (CST) leading to degeneration of the fibres which show characteristic hyper intensities along the tracts leading to the “wine glass sign”. Patients with ALS usually present in the 6th decade of life; presentation in pediatric age in the form of juvenile ALS (JALS) being rare.

Loss of function of the ALS protein SigR1 leads to ER pathology associated with defective autophagy and lipid raft disturbances.

Intracellular accumulations of altered, misfolded proteins in neuronal and other cells are pathological hallmarks shared by many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Mutations in several genes give rise to familial forms of ALS. Mutations in Sigma receptor 1 have been found to cause a juvenile form of ALS and frontotemporal lobar degeneration (FTLD). We recently described altered localization, abnormal modification and loss of function of SigR1 in sporadic ALS. In order to further elucidate the molecular mechanisms underlying SigR1-mediated alterations in sporadic and familial ALS, we extended our previous studies using neuronal SigR1 knockdown cell lines. We found that loss of SigR1 leads to abnormal ER morphology, mitochondrial abnormalities and impaired autophagic degradation. Consistent with these results, we found that endosomal trafficking of EGFR is impaired upon SigR1 knockdown. Furthermore, in SigR1-deficient cells the transport of vesicular stomatitis virus glycoprotein is inhibited, leading to the accumulation of this cargo protein in the Golgi apparatus. Moreover, depletion of SigR1 destabilized lipid rafts and associated calcium mobilization, confirming the crucial role of SigR1 in lipid raft and intracellular calcium homeostasis. Taken together, our results support the notion that loss of SigR1 function contributes to ALS pathology by causing abnormal ER morphology, lipid raft destabilization and defective endolysosomal pathways.

Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor.

ALS2 is the gene mutated in a recessive juvenile form of amyotrophic lateral sclerosis (ALS2). ALS2 encodes a large protein termed alsin, which contains a number of predicted cell signaling and protein trafficking sequence motifs. To gain insight into the overall function of alsin and to begin to evaluate its role in motor neuron maintenance, we examined the subcellular localization of alsin and the biochemical activities associated with its individual subdomains. We found that the Vps9p domain of alsin has Rab5 guanine nucleotide exchange activity. In addition, alsin interacted specifically with and acted as a guanine nucleotide exchange factor for Rac1. Immunofluorescence and fractionation experiments in both fibroblasts and neurons revealed that alsin is a cytosolic protein, with a significant portion associated with small, punctate membrane structures. Many of these membrane structures also contained Rab5 or Rac1. Upon overexpression of full-length alsin, the overexpressed material was largely cytosolic, indicating that the association with membrane structures could be saturated. We also found that alsin was present in membrane ruffles and lamellipodia. These data suggest that alsin is involved in membrane transport events, potentially linking endocytic processes and actin cytoskeleton remodeling.