Fig. 3

Possible roles for cerebrospinal fluid in ALS. Abnormal CSF dynamics could have important implications in ALS, with both glymphatic clearance and glymphatic influx possibly involved. a–d Reduced glymphatic clearance could result in the accumulation of various neurotoxic factors, notably that of major pathogenic proteins, including TDP-43 and SOD1. A rise in the levels of CSF components such as glutamate, inflammatory factors and other toxic metabolites could also favour an increasingly toxic interstitial environment (ISF: interstitial fluid). e Given the importance of glymphatic function in lipid transport, impaired clearance or influx may possibly affect the regulation of lipid metabolism. f Impaired glymphatic influx could also influence pharmacokinetics, particularly in the context of intrathecally administered drugs, and may therefore deserve investigation in ALS neurotherapeutics. g Lastly, various lines of evidence suggest that the CSF circulation could act as an important medium for the spread of the disease, with a possible link to proteostasis. Note Shape sizes are weighted by their relative significance