Diseases and Disorders

Protein Dysregulation in Amyotrophic Lateral Sclerosis

Sarah Shirley


Amyotrophic Lateral Sclerosis, also known as Lou Gehrig’s Disease, is a motor degenerative disease that causes loss of motor function. Several mechanisms, such as inflammation, prolonged excitation via excess glutamate, and disruption of mitochondrial function, have been proposed to contribute to the pathology of ALS.  However, there has yet to be a definite understanding of the pathological mechanism by which Amyotrophic Lateral Sclerosis develops. Protein aggregation has been noted as a pathological trigger of various neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease [1]. This article investigates the pathological mechanisms in which protein aggregation develops and causes Amyotrophic lateral Sclerosis.


Amyotrophic Lateral Sclerosis Overview

     Amyotrophic Lateral Sclerosis (ALS) was first described in 1869 by the French neurologist Jean-Martin Charcot and ultimately became known as Lou Gehrig’s disease after the famous baseball player was diagnosed with it [2]. With a prevalence of 4-6 per 100,000 people, ALS is a progressive neurodegenerative disorder characterized by the death of motor neurons, which leads to the loss of voluntary movements as well as breathing, eating, or walking complications [3]. This fatal disease leaves the patient with an average lifespan of 3-5 years after onset. The two types of ALS are familial and sporadic, consisting of 5% and 95% of cases respectively [4].


Protein Aggregation

     The toxic mechanism that causes Amyotrophic Lateral Sclerosis has long been unknown. Proposed hypotheses have included glutamate toxicity and oxidative distress. Most prominently, the key pathological feature that has been implicated is ubiquitinated protein aggregation, which degenerates motor neurons [5]. Protein aggregation was first taken into consideration as a main contributor of the toxic mechanism of ALS through the discovery of the SOD1 (superoxide dismutase) aggregate in the spinal cord of a familial ALS (fALS) patient [6].

     One proposed control machinery that is thought to exacerbate protein aggregation is chaperones, which are upregulated in motor neuron protein aggregates and function in protein aggregation. These molecules have been implicated in the aggregative mechanism and enhanced toxicity of proteins, such as pTDP-43 C-terminal fragments [3]. Reactive astrocytes also have been noted to contribute to protein aggregation. When stressed, astrocytes display changed morphology and properties, thus becoming “reactive.” Co-cultures of astrocytes with motor neurons induce protein aggregation and motor neuron degeneration and survival. Astrocytes, when reactive, increase secretion of inflammatory factors along with enhancing excitotoxicity due to excessive postsynaptic stimulation [6].


Characteristics of Protein Aggregates

     Predominantly, ubiquitinated protein aggregates are characterized to be Lewy body-like hyaline inclusions (LBHIs), which are randomly oriented filaments covered by fine granules or skein-like inclusions. Bunina bodies, characterized by eosinophilic, ubiquitin-negative, round hyaline inclusions without a halo, are surrounded by tubular structures and amorphous dense structures [5]. Some protein aggregative variants are outlined below:

     SOD1 is understood to protect cells from oxidative distress and is causative for 23.5% of familiar and 7% of sporadic cases of ALS. A study from Cornell using pulsed ESR spectroscopy found that copper deficiencies from SOD1 mutation cause protein instability through structural deconformation. Mice injected with hSOD1 protein aggregation developed ALS-like symptoms, developing first in the spinal cord and then progressing to other motor organs after 100 days [7].  In spinal cord samples, SOD1 proteins were found in fALS and sALS patients to be Lewy body-like, fibrilized, and ubiquitinated {5}.

     A notable form of protein aggregation in ALS is TDP-43, which is localized in the nucleus. TDP-43 binds protein to DNA and RNA and has functions of miRNA synthesis and transcriptional repression. Purified TDP-43 depends on the C-terminal glycine-rich domain. Protein inclusions of TDP-43 have been found in the spinal cord, frontal cortex, and glia. They are characterized to be skein-like with hyper-phosphorylated C-terminal fragments [8].


Further Research

     Greater understanding of protein aggregation mechanisms in ALS will aid in developing new therapeutics and targeting strategies for ALS. Questions that should be considered when investigating protein aggregation in ALS include how to suppress and detect protein aggregation in ALS patients. Moreover, different structures of protein aggregates from different gene variants, along with how protein aggregation interplays with the disease mechanism of ALS as a whole, should be considered.


  1. Ramesh, N., & Pandey, U. B. (2017). Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand. Frontiers in Molecular Neuroscience, 10, 263. http://doi.org/10.3389/fnmol.2017.00263

  2. Elaheh Ekhtiari Bidhendi, Johan Bergh, Per Zetterström, Peter M. Andersen, Stefan L. Marklund, and Thomas Brännström (2016, June 1). Two Superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease. Retrieved from https://www.jci.org/articles/view/84360

  3. Pratibha Tripathi, et.al (July 13, 2017). Reactive Astrocytes Promote ALS-like Degeneration and Intracellular Protein Aggregation in Human Motor Neurons by Disrupting Autophagy through TGF-β1. Retrieved from http://www.cell.com/stem-cell-reports/fulltext/S2213-6711(17)30271-0

  4. Blokhuis, A. M., Groen, E. J. N., Koppers, M., van den Berg, L. H., & Pasterkamp, R. J. (2013). Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathologica, 125(6), 777–794. http://doi.org/10.1007/s00401-013-1125-6

  5. What is ALS? (n.d.). Retrieved from http://www.alsa.org/about-als/what-is-als.html

  6. Kalmar, B., & Greensmith, L. (2017). Cellular Chaperones As Therapeutic Targets in ALS to Restore Protein Homeostasis and Improve Cellular Function. Frontiers in Molecular Neuroscience, 10, 251. http://doi.org/10.3389/fnmol.2017.00251

  7. Armon, Carmel. (22/4/2018 ). Amyotrophic Lateral Sclerosis. https://emedicine.medscape.com. Retrieved May 6, 2018

  8. Irvine, G. B., El-Agnaf, O. M., Shankar, G. M., & Walsh, D. M. (2008). Protein Aggregation in the Brain: The Molecular Basis for Alzheimer’s and Parkinson’s Diseases. Molecular Medicine, 14(7-8), 451–464. http://doi.org/10.2119/2007-00100.Irvine

Sarah Shirley

Sarah Shirley

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