Motor neuron disease (also known as amyotrophic lateral sclerosis) is an enigmatic adult-onset neurodegenerative disease that is progressive and incurable. MND is characterised by the loss of motor neurons, consequently leading to muscular paralysis and invariably death. Progressive accumulation of specific misfolded protein species including superoxide dismutase 1 (SOD1)  is a hallmark of both sporadic and familial forms of ALS^[1]. Cell death in ALS is reported to spread in an ordered and progressive manner throughout the nervous system causing a gradient of pathology from site of onset ^[2]. In support of these findings, it has been shown that mutant forms of SOD1 can promote cell to cell propagation of aggregation after being released into the extracellular environment via an unknown mechanism(s)^[3]. We propose that SOD1 aggregates activate a macropinocytosis-like mechanism in neurons that normally are unable to engulf large particles such as protein aggregates. Using scanning electron microscopy, it was observed that SOD1 aggregates cause cytoplasmic membrane perturbations in the form of ruffles and membrane blebbing in neurons. The interaction of these aggregates with neurons also appears to directly stimulate dextran uptake and Rac1 activation. Inhibition of key regulators of macropinocytosis including actin reorganisation and activity of Na⁺/H⁺ exchangers by rottlerin and 5-​(N-​Ethyl-​N-​isopropyl)​amiloride (EIPA) respectively resulted in a significant reduction in the uptake of SOD1 aggregates into neurons. Furthermore, by selectively permeabilising cells using digitonin, it was shown that SOD1 aggregates can enter into the cytosol of neurons. Overall, these data indicate for the first time that the primary mechanism(s) of SOD1 aggregate uptake may involve aggregate-mediated activation of a macropinocytosis-like process and that misfolded SOD1 may be capable of interacting with other proteins in the cytosol to further transmit the misfolding pathology to other cytosolic soluble proteins, similar to the prion protein.