Question

How homeostatic imbalance results in ALS symptoms?

Answer 1

Protein homeostasis (proteostasis), the correct balance between production and degradation of proteins, is essential for the health and survival of cells. Proteostasis requires an intricate network of protein quality control pathways (the proteostasis network) that work to prevent protein aggregation and maintain proteome health throughout the lifespan of the cell. Collapse of proteostasis has been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), the most common adult onset motor neuron disorder.

The proteostasis network is a complex regulatory network that maintains proteostasis. The proteostasis network consists of several pathways that control protein biosynthesis, folding, trafficking, and clearance (degradation) and responds to specific protein stress pathways such as the unfolded protein response (UPR) in the endoplasmic reticulum (ER), the mitochondrial UPR and the cytosolic heat shock response.

ALS is a progressive adult onset motor neuron disease characterized by selective degeneration of upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. The progressive deterioration of the motor system leads to muscle wasting, paralysis and eventual premature death, most commonly due to respiratory failure. Death occurs on average within approximately 3 years of symptom onset.

Intracellular proteinaceous inclusions are a hallmark neuropathological feature of ALS. Inclusions are found in both degenerating neurons and surrounding glia and are found not only in the brainstem and spinal cord, but also in the cerebellum, hippocampus, and the frontal and temporal lobes, The most common inclusions are of ubiquitinated proteins, which are found in both the upper and lower motor neurons and are suggestive of defects in protein turnover.

Molecular chaperones assist protein folding and help maintain proteins in their native folded state. In addition, they function in proteostasis to facilitate protein unfolding and disaggregation, and the targeting of terminally misfolded proteins for degradation. In relation to neurodegeneration, perhaps the key function of chaperones is to prevent protein aggregation under conditions of stress. Altered chaperone function has been implicated in ALS.