Histological changes in the rat brain and spinal cord following prolonged intracerebroventricular infusion of cerebrospinal fluid from amyotrophic lateral sclerosis patients are similar to those caused by the disease

Human Spinal Motor Neurons Are Particularly Vulnerable to Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients

“…Intrathecal infusion of ALS-CSF in an in vivo rat model caused pathological abnormalities similar to those found in the postmortem sections of ALS patients, namely accumulation of cytoplasmic TDP-43, indicating a spread of the disease via CSF [4]. Further investigations showed the induction of TDP-43 aggregation in the case of ALS-FTD-CSF using a glioblastoma cell model [8].…”

“…A multitude of phenotypes could be observed by this including aggregation of transactive response DNA binding protein 43 kDA (TDP-43) in the case of ALS-frontotemporal dementia (FTLD)-CSF [8], neurofilament abnormalities [9], gliosis [10], endoplasmic reticulum (ER)-stress [6], mitochondrial dysfunction [11] and Golgi fragmentation [6,12]. In addition, intrathecal infusion of ALS-CSF in an in vivo rat model mimicked neuropathological changes similar to the ones found in postmortem tissue of ALS patients [4]. Furthermore, interesting is the fact that not only CSF but also extracellular mutant superoxide dismutase 1 (SOD1) itself was able to induce Golgi fragmentation and the inhibition of ER-Golgi trafficking [13].…”

“…Several studies have demonstrated diverse pathological effects of ALS-CSF in different in vivo and in vitro models [3][4][5][6][7]. These models mainly include primary murine cortical or spinal MN cultures and spinal cord neuroblastoma hybrid cell line NSC34 cultures.…”

Cerebrospinal fluid cytotoxicity does not affect survival in amyotrophic lateral sclerosis

“…[17][18][19] A previous article by our group has shown that prolonged administration of cytotoxic CSF from patients with ALS produces pathological changes associated with human disease in rats. 20 However, the influence of CSF cytotoxicity and its mechanism in human disease is unknown. Our study is the first to evaluate this issue and found no differences in survival rates between patients with or without cytotoxic CSF.…”

40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

“…With TDP-43 known to be present in ALS-CSF (Majumder et al, 2018), several attempts have also been made to establish the impact of ALS-CSF exposure on TDP-43 aggregation, and the associated downstream features. Intraventricular injection of CSF from ALS patients into rats resulted in the formation of cytosolic inclusions of TDP-43 co-localizing with ubiquitin (Gomez-Pinedo et al, 2018). In a later study, ALS-CSF injection was also found to induce TDP-43 proteinopathy as well as motor and cognitive disability in hTDP43 mice (Mishra et al, 2020).…”