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Review
. 2016 Feb;31(2):225-34.
doi: 10.1002/mds.26428. Epub 2015 Sep 21.

Combination therapies: The next logical Step for the treatment of synucleinopathies?

Elvira Valera  1 , Eliezer Masliah  1   2
Affiliations
Review

Combination therapies: The next logical Step for the treatment of synucleinopathies?

Elvira Valera et al. Mov Disord. 2016 Feb.

Abstract

Currently there are no disease-modifying alternatives for the treatment of most neurodegenerative disorders. The available therapies for diseases such as Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), in which the protein alpha-synuclein (α-Syn) accumulates within neurons and glial cells with toxic consequences, are focused on managing the disease symptoms. However, using strategic drug combinations and/or multi-target drugs might increase the treatment efficiency when compared with monotherapies. Synucleinopathies are complex disorders that progress through several stages, and toxic α-Syn aggregates exhibit prion-like behavior spreading from cell to cell. Therefore, it follows that these neurodegenerative disorders might require equally complex therapeutic approaches to obtain significant and long-lasting results. Hypothetically, therapies aimed at reducing α-Syn accumulation and cell-to-cell transfer, such as immunotherapy against α-Syn, could be combined with agents that reduce neuroinflammation with potential synergistic outcomes. Here we review the current evidence supporting this type of approach, suggesting that such rational therapy combinations, together with the use of multi-target drugs, may hold promise as the next logical step for the treatment of synucleinopathies.

Keywords: Parkinson's disease; alpha-synuclein; combination therapy; synucleinopathies; therapeutics.

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Conflict of interest statement

Conflict of interest

The authors declare that they have no conflict of interest, support or financial issues.

Figures

Figure 1
Figure 1. Windows for therapeutic intervention in synucleinopathies
Hypothetical disease progression in stages postulated for PD and other synucleinopathies, including α-syn deposition, death of selected neuronal populations, neuroinflammation and cognitive and motor deficits. Suggested treatments that could be suitable for each therapeutic window of opportunity are depicted below.
Figure 2
Figure 2. Disease-modifying therapeutic strategies focused on intracellular α-syn accumulation
Intracellular α-syn levels are regulated by the balance between α-syn synthesis, aggregation and clearance. Strategies to reduce α-syn accumulation include decreasing its synthesis (−) with siRNA or miRNAs, reducing its aggregation (−) using anti-aggregation agents or post-translational modifications, and/or activating clearance mechanisms (+) such as autophagy.
Figure 3
Figure 3. Potential therapeutic interventions for the treatment of synucleinopathies
α-syn aggregation can take place either in the cytoplasm or in association with the cellular membrane of neuronal cells. Interestingly, α-syn oligomers and fibrils, as well as the monomers, can be transferred between cells and induce disease spreading to other brain regions. Propagation of α-syn to astroglial and microglial cells can induce glial activation and neuroinflammation. In MSA, α-syn also accumulates within oligodendrocytes and propagate from these cells to astroglia. Potential therapeutic interventions include immunotherapy against extracellular α-syn; the use of anti-inflammatories to reduce glial neuroinflammation; autophagy inducers to stimulate the clearance of intracellular α-syn; and mechanisms to reduce or compensate neurodegeneration such as L-DOPA, MAO inhibitors, neuroprotective compounds, neurotrophic factors (BDNF, GDNF) or regenerative therapy with stem cells.
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