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In ALS, Multiple Pathways May Converge on ER and Mitochondrial Dysfunction to Cause Neuronal Death Multiple pathways are implicated in ALS with many thought to cause and exacerbate ER stress and mitochondrial dysfunction, two pathways central to neuronal death Mitochondrial death proteins, including BAX, are upregulated in post-mortem ALS spinal cord samples, as are unfolded protein response (UPR) related proteins Genetic causes of ALS, including the most well-known genes SOD1, C9orf72 and TDP43, are mechanistically linked to mitochondrial and ER dysfunction Upper motor neuron Motor cortex Astrocyte TDP43 FUS aggregates Ca Na O-Glutamate Glutamate excitotoxicity lonotropic glutamate receptors Microglia Release of pro-inflammatory cytokines Mitochondrial dysfunction Ca-dependent enzymatic pathways -TCa Na-K pump dysfunction Neuronal death 2K 3Na TNa C9orf72, TARDBP. FUS and SOD1 Oxidative stress lon channel dysfunction Na ER stress Defects in nucleo- cytoplasmic trafficking K 10 EAAT2- Glutamate excitotoxicity Lower motor Schwann cells neuron Mu, X Annals of Neurology 1996, Israelson A et al., 2010; Pickles S and Van de Velde C., 2012; Nishitoh H et al., 2008; Kiskinis E et al., 2014; Farg et al., 2012 Archana P et al., 2019; Huang C et al., 2020; Tan W et al., 2014; Choi SY et al., 2019; Mehta AR et al., 2021; Tsai Y-L et al., 2020; Nakaya T et al., 2018, Montibeller, L. Cell Stress Chaperones. 2018; Manfredi G, Kawamata H. Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis. Neurobiol Dis. 2016;90:35-42. doi:10.1016/j.nbd.2015.08.004; Smith EF, Shaw PJ, De Vos KJ. The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett. 2019;710:132933. doi:10.1016/j.neulet.2017.06.052. mutations Defects in RNA Na processing and Schwann cell defects Defects in protein folding and degradation protein synthesis SOD1 aggregates Neuromuscular Muscle junction Dysfunction of axonal transport systems -Accumulated neurofilament Adapted from Kiernan, M.C., Vucic, S., Talbot, K. et al. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Reviews Neurology 17, 104-118 (2021). https://doi.org/10.1038/s41582-020-00434-z Ca Reversal of Na-Ca exchanger AMYLYX 25

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