Trends in Molecular Medicine
Volume 25, Issue 12, December 2019, Pages 1056-1065
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Opinion
MCL1 as a Therapeutic Target in Parkinson's Disease?

https://doi.org/10.1016/j.molmed.2019.08.009Get rights and content

Highlights

  • 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 degradation

  • A 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.

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.

Section snippets

Exposing the Intrinsic Vulnerability of Midbrain Dopamine Neurons

Underlying the motor symptoms of Parkinson's disease (PD) is the loss of dopaminergic neurons that project from the substantia nigra (SN; see Glossary) to the striatum. These neurons regulate voluntary movement, and their loss leads to tremor, progressive rigidity, loss of postural stability, and bradykinesia [1]. Current treatments are aimed at relieving clinical symptoms. There is no cure. The 'gold standard' in the treatment of PD is oral supplementation with L-DOPA

The Importance of Bcl2 Proteins in Dopaminergic Neurons

In one of the first studies addressing the role of Bcl2 factors (a list of the best-known Bcl2 factors is given in Table 1) in mouse dopamine neurons, a protective effect of Bcl2 expressed from the promoter of the gene (Th) encoding tyrosine hydroxylase (Th) was shown. Ectopic expression of Bcl2 resulted in an increased number of dopaminergic neurons and also protected against cell loss following quinolinic acid administration in the striatum, thus providing a proof-of-principle that Bcl2

Mcl1 as a Survival Factor in Dopamine Neurons

Previous studies have shown that Mcl1 is highly expressed in neurons of the developing brain and that its expression drops dramatically in the adult, suggesting a role of lesser importance at this stage [22]. In contrast to Mcl1, the prosurvival Bcl2 factor Bcl-xL remains highly expressed in adult neurons and has been shown to be crucial for the survival of cortical neurons 22, 23. However, despite its overall low expression in the adult brain, recent studies support an important role for Mcl1

Targeting Mcl1: The Ubiquitin Proteasome System, E3 Ubiquitin Ligases, and Deubiquitinases

Mcl1 harbors a large N-terminal region packed with regulatory motifs. Interestingly, many of these motifs influence the stability of Mcl1. Mcl1 is a short-lived protein and is rapidly degraded, which is attributed to the ubiquitin proteasome system 27, 28. Depending on the cell type studied, Mcl1 half-life ranges from 1 h to 5 h. Human MCL1 contains 12 lysine residues, of which five are described to be extensively involved in its degradation: K5, K40, K136, K194, and K197 [29]. By comparison,

Targeting Mcl1 with Small Molecules and Peptides as a Therapeutic Approach

The BCL2 family has been the focus of drug discovery efforts in oncology, with the objective of inhibiting the protective guardian BCL2 family members to induce apoptosis in tumors. To our knowledge, no drug discovery or rational drug design effort has aimed to achieve the opposite – the selective enhancement of antiapoptotic BCL2 ‘guardian’ function to protect death-prone cells.

Concluding Remarks

Halting the progressive loss of dopaminergic neurons in the SN is a major challenge in PD research. Causative mutations have been identified in a minor fraction of PD patients, but the majority of PD cases remain idiopathic with an identical end-result: neurodegeneration. By interfering with crucial components necessary for cell death, a generalized method for halting neurodegeneration in PD could be realized. Accumulating evidence supports a role for BCL2 proteins and mitochondria-dependent

Acknowledgments

This work has been supported by Stichting ParkinsonFonds, The Netherlands.

Glossary

Agonists
chemicals that invoke an action response, in other words activators. By contrast, antagonists inhibit a response.
Bioenergetics
pathways which involve energy in organisms, such as growth, development, and metabolism. ATP is the main energy source used during these processes.
Bradykinesia
a slowness of movement that is characteristic of Parkinson’s disease (PD) symptoms.
Caspases
specialized proteins that are known for their cleavage activity in the apoptosis pathway.
Degron
the part of a

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