La infusión intracerebroventricular prolongada de líquido cefalorraquídeo procedente de pacientes con esclerosis lateral amiotrófica provoca cambios histológicos en el cerebro y la médula espinal de la rata similares a los hallados en la enfermedad

Abstract

Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease.

Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies

“…While the cause of these findings remains unclear, they nevertheless suggest the presence of one or more potentially toxic factors in ALS–CSF, with possible involvement in disease spread ( Smith et al , 2015 ). Consistent with this possibility, recent in vivo evidence also includes pathological changes being observed distant to the CSF infusion site ( Gomez-Pinedo et al , 2018 ).…”

“…In vitro results also need to be complemented by in vivo evidence, which have to date revealed various changes following CSF infusion, including neurofilament phosphorylation, endoplasmic reticulum stress, as well as motor dysfunction ( Deepa et al , 2011 ; Vijayalakshmi et al , 2011 ; Shanmukha et al , 2018 ). Although the observed changes have been reported to be histologically similar to sporadic ALS cases ( Gomez-Pinedo et al , 2018 ), whether CSF toxicity studies accurately capture the mechanisms involved in ALS pathophysiology, and could serve as an important model for ALS, is not yet clear. Various lines of evidence, however, hint at a potential contribution of CSF in the spread of the disease in ALS patients, with one major appeal for this model being its explanatory potential with respect to clinical observations ( Smith et al , 2015 ).…”

“…Amongst the many lines of enquiry aiming to address this question, several studies have suggested that a neurotoxic cerebrospinal fluid (CSF) profile could be implicated in the disease process ( Shaw, 2002 ; Matias-Guiu et al , 2010 ; Sumitha et al , 2019 ; Tokuda et al , 2019 ). CSF from ALS patients has in fact been shown to exert cytotoxicity in vitro ( Tikka et al , 2002 ; Vijayalakshmi et al , 2009 ; Barber et al , 2011 ; Sumitha et al , 2019 ), and to provoke wide-ranging pathology, from neurofilament phosphorylation to musculoskeletal changes, when administered in vivo ( Shahani et al , 2004 ; Gomez-Pinedo et al , 2018 ; Shanmukha et al , 2018 ). While the cause of these findings remains unclear, they nevertheless suggest the presence of one or more potentially toxic factors in ALS–CSF, with possible involvement in disease spread ( Smith et al , 2015 ).…”

Defining novel functions for cerebrospinal fluid in ALS pathophysiology

“…Moreover, intrathecal injection of ALS-CSF led to changes in the Golgi complex [158], potentially affecting protein trafficking and causing endoplasmic reticular stress [196]. Histologically, close similarities were observed between tissue exposed to ALS-CSF and sporadic ALS cases [68]. ALS-CSF was also found to produce phenotypic changes, with rats subjected to intraventricular injections experiencing motor dysfunction [165].…”

“…Accepting inherent limitations in patient studies, including sample heterogeneity, and that CSF concentration may not reflect cellular levels, these in vitro and in vivo studies nonetheless show that ALS-CSF is toxic to neurons and possesses pro-inflammatory properties [136]. The in vivo finding of toxicity distant to the site of CSF injection also raises a potential role for CSF in disease spread [68], a possibility supported by recent findings demonstrating the onset of motor and cognitive decline, as well as TDP-43 proteinopathy, following ALS-CSF infusion in mice [125].…”