Sporadic amyotrophic lateral sclerosis: new hypothesis regarding its etiology and pathogenesis suggests that astrocytes might be the primary target hosting a still unknown external agent

Abstract

This article briefly describes the already known clinical features and pathogenic mechanisms underlying sporadic amyotrophic lateral sclerosis, namely excitoxicity, oxidative stress, protein damage, inflammation, genetic abnormalities and neuronal death. Thereafter, it puts forward the hypothesis that astrocytes may be the cells which serve as targets for the harmful action of a still unknown environmental agent, while neuronal death may be a secondary event following the initial insult to glial cells. The article also suggests that an emergent virus or a misfolded infectious protein might be potential candidates to accomplish this task. Key words: ALS, SALS, pathogenesis, astrocytes.Esclerosis lateral amiotrófica esporádica: nueva hipótesis relacionada con su etiología y patogenia que sugiere que los astrocitos podrían ser el blanco primario alojando un agente nocivo aun desconocido RESUMEN El artículo presente describe, brevemente, las características clínicas y los mecanismos patogénicos de la esclerosis lateral amiotrófica esporádica, tales como la excitotoxicidad, el stress oxidativo, el daño proteico, la inflamación, las anormalidades genéticas y la muerte neuronal. Luego de ello, sugiere la posibilidad hipotética de que los astrocitos podrían ser el blanco primario de la acción de una agente ambiental, externo, aún desconocido, y que la muerte neuronal aconteciera secundariamente a ese daño astrocitario inicial. El artículo concluye discutiendo la posibilidad de que un virus ambiental o endógeno o una proteína mal plegada, que adquiriera características de infectividad, puedan ser la causa de la enfermedad. Palabras-clave: esclerosis lateral amiotrófica, esclerosis lateral amiotrófica esporádica, patogenia, astrocito.

Are astrocytes executive cells within the central nervous system?

“…Therefore, it becomes reasonable to assume that the astrocytes that influence a particular population of neurons devoted to a specific function constitute a singular population, only devoted to those types of cells 2,40 ; in this regard they should have their architecture and a metabolism particularly suited to the sustenance and control of those neurons' needs and activities.…”

“…The physiological properties of astrocytes have been the subject of comprehensive reviews written in the last few years 1 , while other authors have highlighted the role that astrocytes play in the development of diseases previously attributed solely to neurons 2,3 .…”

Is amyotrophic lateral sclerosis a primary astrocytic disease?

“…In a previous paper [1], we suggested that sporadic amyotrophic lateral sclerosis (SALS) was due to the action of a still unrecognised agent whose primary target would be the population of astrocytes related to motor neurons; this initial damage would start the sequence of pathological events in this illness, finally leading to death of the motor neurons. In addition, we proposed that the critical malfunction of the astrocytes was an inability to manufacture the EAAT2 (GTL-1) glutamate transporter [2,3]; more recent findings in patients and animal models now allow further consideration of this proposal.…”

Far beyond the motor neuron: the role of glial cells in amyotrophic lateral sclerosis

“…In motor neuron disease linked to TAR DNA-binding protein 43 (TDP43), fused in sarcoma protein (FUS), ALS2 gene, VAPB gene, OPTN gene and C9ORF72 gene (chromosome 9 open reading frame 72) mechanisms 7,9 , few data regarding the involvement of glial cells are available, compared with cases related to SOD1 gene mutations.…”

“…effect) 7 . This review aims to summarize the most important data established on the role of glial cell types in ALS.…”