Geldanamycin is a benzoquinone ansamycin antibiotic that targets HSP90, disrupting its chaperone function and leading to the degradation of oncogenic and neurotoxic client proteins. While extensively studied in oncology, geldanamycin has demonstrated neuroprotective effects in models of Parkinson's disease. It reduces alpha-synuclein toxicity in dopaminergic neurons and destabilizes mutant p53, a protein linked to neuronal apoptosis. Geldanamycin also inhibits c-Jun N-terminal kinase (JNK) signaling and suppresses hypoxia-induced stress responses, both of which are implicated in neurodegeneration. By modulating protein folding, stress signaling, and autophagy, geldanamycin offers a mechanistic framework for targeting neurodegenerative pathways. Despite its therapeutic potential, clinical use is limited by hepatotoxicity and poor solubility, prompting the development of safer analogs such as 17-AAG and 17-DMAG.
