Objective/Rationale:
Posiphen is a well-tolerated translation blocker of the Parkinson’s disease causative protein alpha-synuclein (SNCA) via the 5’untranslated region (5’UTR) in its mRNA. Our goal is to identify which of fifteen close analogs of posiphen and (-)bisnorcymserine more optimally limits brain SNCA levels (with Dr. Nigel Greig, NIA). Analogs will be tested to lower SNCA in SH-SY5Y cells and primary hippocampal neurons from transgenic models expressing the human SNCA transgene with intact 5’UTR sequences.
Project Description:
Posiphen is a well-tolerated inhibitor of APP translation and amyloid burden undergoing phase II clinical trials for Alzheimer’s Disease. However, we found that posiphen also inhibited alpha-synuclein (SNCA) expression via 5’ leader sequences in its transcript. Using cultured neural cells, posiphen caused Iron-regulatory Protein-1 (IRP-1) to super-repress translation of neural SNCA levels. Fibrilar SNCA mediates neurotoxicity to dopaminergic neurons during PD, thus we will find which of 15 top well-tolerated analogs of posiphen exerts the most favorable therapeutic inhibition of SNCA expression. These analogs will be ranked for their anti SNCA potency using primary hippocampal neurons from a transgenic model in which the SNCA is controlled by intact translational regulatory sequences that best reflect events in humans (with Dr. Robert Nussbaum, UCSF).
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Fibrilized alpha-synuclein is associated with striatal neuronal death during Parkinson’s disease. Posiphen underwent clinical trials for AD as an anti amyloid drug but posiphen also repressed the expression of the PD specific neural SNCA by blocking its translation via 5’ leader sequences. We will pursue the medicinal development of posiphen as a protective agent against PD lesioning in vivo in an alpha-synuclein PD transgenic model that maintains the correct 5’untranslated region in SNCA mRNA.
Anticipated Outcome:
We will rank the ex vivo capacity of analogs of posiphen to best super-repress translation the SNCA transcript in cortical neurons from PAC-Tg-SNCA mice. This therapeutic route for PD is selective translational repression of SNCA by Iron-regulatory-Protein-1 (IRP1). Characterization of new therapeutic SNCA translational inhibitors will also provide probes to mechanistically address how IRP1 binds to the alpha-synclein transcript to repress SNCA translation and thus reduce accumulation of this neuropathogenic protein in neurons.