Protein Misfolding Diseases and Environmental Triggers
Neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, ALS, and prion diseases share a common pathological theme: aberrant protein misfolding and aggregation producing toxic species. Environmental factors that impair proteostasis—the cellular machinery maintaining protein folding quality—may increase susceptibility to or accelerate progression of these diseases.
PFAS Effects on Proteostasis
PFAS compounds disrupt endoplasmic reticulum (ER) stress responses and unfolded protein response (UPR) pathways that normally manage misfolded proteins. Impaired UPR allows misfolded proteins to accumulate rather than being refolded or degraded. This proteostasis disruption creates cellular conditions permissive for the amyloid aggregation that drives multiple neurodegenerative pathologies.
Autophagy Impairment and Aggregate Clearance
Autophagy—the cellular self-digestion process that clears protein aggregates—is impaired by PFAS-induced lysosomal dysfunction. Reduced autophagic flux allows toxic protein aggregates (tau tangles, alpha-synuclein Lewy bodies, TDP-43 inclusions) to accumulate more rapidly. This aggregate clearance failure represents a common mechanism through which PFAS could accelerate multiple distinct neurodegenerative diseases.
Cross-Disease Implications
The proteostasis disruption mechanism is disease-agnostic—it could contribute to Alzheimer’s, Parkinson’s, and ALS depending on which protein aggregation pathway is genetically or otherwise primed. Reducing PFAS exposure may represent a cross-disease neuroprotective strategy relevant to anyone with genetic risk for protein misfolding neurodegenerative conditions