MCL1 as a Therapeutic Target in Parkinson's Disease?

Dopamine neurons in the substantia nigra (SN) pars compacta are selectively lost during the progression of Parkinson’s disease (PD). Recent work performed on the role of the Bcl2 family (highly specialized proteins which control cellular survival and death) in midbrain dopamine neurons has led to the identification of the Bcl2 factor Mcl1 as a weak link in the survival of these neurons. We hypothesize that the regulation of BCL2 proteins may explain this selective vulnerability, and may even provide a novel therapeutic opportunity – strengthening weak links such as MCL1 could result in a delay or complete abrogation of cell death during PD. The motor symptoms of PD are caused by loss of dopamine neurons in the SN of the brain. There is no cure, nor can the progressive loss of neurons be halted.Several forms of regulated cell death have been attributed to this loss of dopamine neurons, of which apoptosis has emerged as a prominent candidate.Mitochondria-dependent apoptosis is controlled by Bcl2 factors. Parkin, an E3 ligase, targets the proapoptotic Bcl2 protein Bax for degradationA reduction of Mcl1, an antiapoptotic Bcl2 protein, in the parkin knockout mouse leads to loss of dopamine midbrain neurons.Functional Mcl1 inhibition with a chemical compound results in apoptosis of neuronal cells and of dopamine neurons in the mouse SN.Enhancing Mcl1 may be a therapeutic strategy to delay apoptosis of dopamine neurons in PD.