Mutated UBQLN2 and C9orf72 form aggregates that associate with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using biophysical methods, biochemical techniques, and longitudinal fluorescence cellular analysis, we studied the molecular determinants that precipitate the aggregation of these proteins. We found that dipeptide repeat protein (DRP) products of the mutant C9orf72 are direct predictors of neuronal toxicity. Moreover, external application of some, but not all, C9orf72-associated DRPs causes significant neuronal toxicity. This toxicity is dependent on both the propensity of these proteins to self-aggregate and on the types of aggregate structures that they form. With regard to UBQLN2, we find that the ubiquitin-associated (UBA) domain at the C-terminus precipitates the aggregation. On the other hand, ubiquitin-like domain at N-terminus is protective. We also observed increased aggregation of the mutant UBQLN2, which also correlates with neurotoxicity. These results reveal key molecular features that drive protein aggregation of UBQLN2 and DPRs and suggest correlative relationship between aggregation and neurotoxicity.