Defining novel functions for cerebrospinal fluid in ALS pathophysiology
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Defining novel functions for cerebrospinal fluid in ALS pathophysiology Koy Chong Ng Kee Kwong1,2,3†, Arpan R. Mehta1,2,3,4,5† , Maiken Nedergaard6,7 and Siddharthan Chandran1,2,3,4,8*
Abstract Despite the considerable progress made towards understanding ALS pathophysiology, several key features of ALS remain unexplained, from its aetiology to its epidemiological aspects. The glymphatic system, which has recently been recognised as a major clearance pathway for the brain, has received considerable attention in several neurological conditions, particularly Alzheimer’s disease. Its significance in ALS has, however, been little addressed. This perspective article therefore aims to assess the possibility of CSF contribution in ALS by considering various lines of evidence, including the abnormal composition of ALS-CSF, its toxicity and the evidence for impaired CSF dynamics in ALS patients. We also describe a potential role for CSF circulation in determining disease spread as well as the importance of CSF dynamics in ALS neurotherapeutics. We propose that a CSF model could potentially offer additional avenues to explore currently unexplained features of ALS, ultimately leading to new treatment options for people with ALS. Keywords: Glymphatic system, Cerebrospinal fluid, Amyotrophic lateral sclerosis, Motor neuron disease, Frontotemporal dementia, Ageing Introduction Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disorder characterised by the selective death of motor neurons. Although the underlying cause of ALS is unknown, recent discoveries in the genetics and molecular pathology of ALS have provided important new insights. These include the finding that monogenetic causes of ALS—accounting for approximately 10% of cases—are phenotypically and pathologically largely indistinguishable from sporadic ALS. Furthermore, over 97% of ALS cases and half of frontotemporal dementia (FTD) are pathologically defined by cytoplasmic mis-accumulation of insoluble TDP-43, *Correspondence: [email protected] † Koy Chong Ng Kee Kwong and Arpan R. Mehta have contributed equally to this work 2 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh bioQuarter, Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK Full list of author information is available at the end of the article
leading to these disorders being classified as TDP-43 proteinopathies [135]. Although much remains to be established about ALS pathophysiology, multiple mechanisms are implicated including proteostasis, glutamate excitotoxicity, dysregulation of RNA metabolism, nuclear-cytoplasmic transport and autophagy [16, 36, 73]. Notwithstanding these advances in our mechanistic understanding of ALS, a number of key questions remain unanswered. These include the primary cause of the disease and the significance of ageing as a risk factor, as well as a male predilection [8, 107]. The glymphatic system has recently been recognised as an important clearance pathway for t
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