Neurodegenerative diseases share the unifying features of insoluble protein aggregates and irreversible neuron loss. Parkinson’s disease (PD) is defined by proteinaceous Lewy bodies—which contain α-synuclein—and loss of dopamine neurons leading to motor dysfunction. Growing evidence implicates α-synuclein aggregation as a causal driver of neurodegeneration in certain forms of PD. However, the precise mechanism(s) by which the process or products of α-synuclein aggregation drive neuron death remains unknown. Better understanding of this key question might further development of neuroprotective therapies for PD and related disorders. To address this gap, we reviewed how the native conformation of α-synuclein relates to its physiological function and roles in pathology. We also examined how the mouse brain proteome and phosphoproteome change in response to α-synuclein aggregation using quantitative proteomics. This revealed that proteomic changes were not widespread, but instead were enriched within certain functional areas. For the first time, we found that the immunoproteasome is induced during aggregation, providing a new tunable target for studying α-synuclein aggregation and its connection to toxicity. We also employed nordihydroguaiaretic acid (NDGA) and analogs to study the chemistry and products of phenolic inhibitors of α-synuclein aggregation. We discovered that oxidation-dependent cyclization is required for NDGA analogs to inhibit α-synuclein aggregation and that this inhibition is caused by modification of α-synuclein monomers that retain their conformational dynamics and lipid interactions. Further, we found that these NDGA analog-modified monomers exert a dominant negative effect on aggregation of untreated α-synuclein, exposing a novel mechanism for inhibiting α-synuclein aggregation. Using transgenic Caenorhabditis elegans, we showed that cyclized NDGA can prevent neurodegeneration driven by α-synuclein. These findings outline a novel paradigm for small molecule inhibition of α-synuclein aggregation wherein they act by stabilizing dynamic α-synuclein monomers, preventing aggregation. This in turn prevents aggregation of untreated α-synuclein and reduces neurodegeneration. Together this work underscores the importance of α-synuclein’s native structural dynamics and provides several novel tools for future use in untangling the relationship between α-synuclein aggregation and neuron loss in PD and related disorders.