Protein Aggregation Diseases

In protein aggregation diseases, the misfolded protein self-associates, which ultimately produces large, insoluble deposits or plaques. Toxic intermediates are formed during this process. This acquisition of a new activity, albeit deleterious, is referred to as a “toxic gain of function.” Several previously unrelated diseases, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, transthyretin amyloidosis, and type 2 diabetes share a common feature of aggregation and deposition of misfolded protein.

In Parkinson’s disease (PD), aggregation and fibrillization of the protein α-synuclein is thought to play a major role in neuronal dysfunction and death of dopaminergic neurons. Mutations in α-synuclein or overexpression of wild type α-synuclein (e.g., by triplication of the genomic locus) cause some rare forms of familial Parkinson’s disease. The mechanism of α-synuclein cytotoxicity is unclear; however, accumulating evidence suggests that small soluble oligomers contribute to neurodegeneration, while Lewy bodies, by sequestering α-synuclein, may be neuroprotective. FoldRx is identifying small molecules that mitigate the toxic effects of α-synuclein with the goal of developing novel, disease-modifying therapies for Parkinson’s disease and other synucleinopathies such as Lewy body dementia.

In addition to the synucleinopathies, FoldRx’s discovery platform has been applied to two additional proteins, huntingtin and TDP-43, that cause neurodegenerative diseases. Huntington’s disease is caused by the expansion of a glutamine-rich region in huntingtin. Disease occurs when the number of glutamine residues exceeds 35-40 residues and increases in severity with the length of the polyQ repeat. TDP-43 has been implicated in both amyotrophic lateral sclerosis and frontal temporal lobar degeneration.