The proteostasis network (PN) represents a sophisticated cellular machinery dedicated to maintaining protein homeostasis, ensuring proper folding, trafficking, and degradation of proteins. This system comprises molecular chaperones, the ubiquitin-proteasome system (UPS), autophagy-lysosomal pathways, and stress-responsive signaling cascades. In neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), the PN becomes overwhelmed, leading to the accumulation of toxic protein aggregates like amyloid-β (Aβ) plaques and α-synuclein fibrils.
Small molecules targeting the PN offer a promising therapeutic strategy to counteract protein aggregation. These compounds can enhance chaperone activity, boost degradation pathways, or inhibit toxic oligomer formation.
Heat shock proteins play a crucial role in preventing protein misfolding. In AD models, HSP70 inducers like geranylgeranylacetone have shown efficacy in reducing Aβ aggregation. Conversely, HSP90 inhibitors such as 17-AAG promote the degradation of tau by redirecting clients to the UPS.
Rapamycin and its analogs (rapalogs) induce autophagy by inhibiting mTORC1, leading to clearance of α-synuclein aggregates in PD models. Trehalose, a disaccharide, enhances autophagy independently of mTOR, offering an alternative pathway for aggregate removal.
Small molecules like IU1 inhibit USP14, a deubiquitinating enzyme, increasing proteasomal degradation of misfolded proteins. This approach has demonstrated reduced tau pathology in transgenic mouse models.
AD is characterized by the accumulation of Aβ plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Pharmacological interventions aim to either prevent aggregation or enhance clearance.
Scyllo-inositol (ELND005) stabilizes Aβ in non-toxic oligomers, reducing plaque formation in preclinical studies. Similarly, small molecule β-sheet breakers like D737 disrupt fibril formation.
Methylene blue derivatives (e.g., LMTM) inhibit tau aggregation and promote its degradation. Kinase inhibitors targeting GSK3β or CDK5 reduce tau hyperphosphorylation, mitigating tangle formation.
PD pathology is driven by α-synuclein aggregation into Lewy bodies. Modulating proteostasis offers multiple therapeutic angles.
Anle138b binds to oligomeric α-synuclein, preventing fibril formation and improving motor symptoms in PD mice. NPT100-18A, a small molecule inhibitor, reduces α-synuclein propagation between neurons.
Compounds like AR7 activate CMA, facilitating the degradation of soluble α-synuclein. This approach has shown promise in reducing neuronal loss in PD models.
Despite progress, several hurdles remain in developing effective PN-modulating drugs:
Bifunctional molecules that simultaneously target protein aggregation and enhance degradation pathways are under investigation. Additionally, CRISPR-based screens are identifying novel PN regulators for therapeutic targeting.
The dynamic interplay between protein misfolding and cellular clearance mechanisms underscores the complexity of neurodegenerative diseases. Small molecules that fine-tune the proteostasis network represent a viable strategy to combat protein aggregation. Future research must focus on patient stratification and personalized therapeutic regimens to maximize efficacy.