Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are genetically-related neurodegenerative diseases pathologically characterized by aggregation of proteins, such as TDP-43, FUS, SOD1, hnRNPs, dipeptide protein repeats, Tau, etc. How these proteins aggregate is unclear—many factors seem to be at play. However, whether and how sugar molecules play a role in this process is unknown. In vitro studies suggested molecular crowding agents, such as dextran, promote the condensation of some of the aforementioned ALS/FTD proteins and induce their aggregation. Given the structural similarity between dextran and glycogen, both of which are polymers of glucose, we propose an intriguing hypothesis that glycogen can function as a crowding agent to induce ALS/FTD protein aggregation, thereby contributing to neurodegeneration. Importantly, glycogen, but not dextran, is a naturally present polysaccharide in mammals, suggesting its role as a crowding agent in physiological conditions. Consistent with this hypothesis, previous studies suggested that glycogen is abnormally upregulated and/or accumulated in ALS/FTD patients and animal models, and our preliminary data suggest that suppressing glycogenosis ameliorate neurodegeneration in a Drosophila model of ALS/FTD. Therefore, we are excited about this hypothesis and propose to further test it in vitro, using recombinant proteins, and in cultured cells and disease models, as well as to verify it in human patients. The proposed studies will reveal the first mechanistic connection between polysaccharide and protein aggregation in ALS and FTD. Importantly, since both glycogen upregulation/accumulation and protein aggregation are implicated in aging and other neurodegenerative diseases, our study may identify a common mechanism by which defects in sugar metabolism contribute to aging and age-related diseases.