Amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig’s Disease, is a rapidly progressing neurodegenerative disorder. The symptoms of the disease usually start between 40-60 years of age. Initial symptoms include mild muscle weakness, cramps, muscle spasms, or muscle stiffness. Although the symptoms are often overlooked at first, symptoms progress until a patient is no longer able to care for himself, eat unassisted, or breathe unassisted. The symptoms of ALS can be attributed to loss of motor neurons; however, like many neurodegenerative disorders, the cause of the degeneration of motor neurons is still unclear.
One possible cause of motor neuron loss is protein misfolding and cellular response to misfolded proteins. The article “Calcium-dependent protein folding in amyotrophic lateral sclerosis,” suggests that changes in the normal calcium levels or signaling causes stress in the cell, which causes the cell to not function properly. The first issue is protein folding. Basically, the cell requires proteins for transport, structure, enzymes to assist reactions in the cell and many other functions. Not only must the building blocks (amino acids) be strung in the right order, but the proteins must also be folded into the correct three-dimensional structure in order for it to function properly. This is where the endoplasmic reticulum (ER) comes into play. When proteins are made, they travel through the ER and are folded along the way. Chaperone proteins, found in the ER, are responsible for folding other proteins into the right shapes. Ca2+ levels in the ER regulate the chaperone proteins’ activity.
When calcium levels in ER deviate from homeostasis, the cell attempts to continue folding proteins correctly. One way to do this is to activate the unfolded protein response (UPR). The UPR tags a protein to tell the ER not to allow the protein to leave until it is properly folded. Without the proper UPR, the cell will experience ER stress for accumulation of proteins, which ultimately results in cell death. Both ER stress and UPR are thought be implicated in ALS pathogenesis. Further research is needed to develop treatments that target the ER and UPR to improve ALS symptoms and survival time. Currently, the average survival time for ALS patients is 3-5 years. By better understanding the progression of this disease, advances could be made in treatment to slow the progression or even cure ALS. Investigating calcium and calcium-dependent folding proteins appears to be a promising direction for ALS research.
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