Emerging Research on Modulators of Alpha-Synuclein Aggregation

Reviewed by: HU Medical Review Board | Last reviewed: March 2017

Alpha-synuclein is a protein that plays a critical role in the development of Parkinson’s disease (PD). While scientists don’t understand the normal function of the protein in the body, they know that in people with PD and some other neurodegenerative diseases, alpha-synuclein clumps together forming aggregates called Lewy bodies. Scientists believe that Lewy bodies are toxic and cause the death of the neurons (nerve cells). These accumulations of alpha-synuclein appear to spread from one neuron to the next. As the number of Lewy bodies increases in the brain and in the nervous system in the body, the symptoms of PD worsen.1,2

Clumping of alpha-synuclein in Parkinson's

Since scientists discovered alpha-synuclein, the protein and the way it clumps together have been areas of focus for research in PD. It is not yet known if the aggregation of alpha-synuclein is the cause of PD, or if some other factor makes the protein clump together. Nevertheless, alpha-synuclein is a potential target for treatment, as researchers believe stopping or slowing the aggregation of this protein could slow the progression of PD.1

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There are different ways researchers are targeting alpha-synuclein. One approach is to break up the Lewy bodies that have formed in the cells through the use of alpha-synuclein aggregation modulators. These modulators stop or reverse the aggregation of the protein, and researchers hope that these modulators will slow or stop the progression of PD.

  • NPT001 – One product currently under clinical investigation is NPT001. In cellular studies, NPT001 has shown the ability to reduce aggregated alpha-synuclein and clear the deposits out of the cells. Now, additional research is needed to test the effectiveness in pre-clinical models. (Pre-clinical studies involve testing the medical treatment on animals to validate the effectiveness and safety before moving to clinical trials in humans.) NPT001 also works on reducing aggregations of the protein tau, which drives Alzheimer’s disease. NPT001 is in additional trials for Alzheimer’s.
  • GBA1 – The GBA1 gene codes for a protein called glucocerebrosidase. Mutations in this gene carry a common genetic risk factor for developing PD. In people with PD (both those with the GBA1 mutation and those without the mutation), there are lower levels of the protein glucocerebrosidase in the central nervous system (CNS). This causes a build-up of alpha-synuclein and the formation of more alpha-synuclein aggregates. Researchers are searching for drugs that will increase the activity of glucocerebrosidase in the CNS, aiming to lower alpha-synuclein levels and slow the disease progression of PD.
  • Conformational change testing – Conformational change is the alteration in the shape of a protein. In the case of PD, the protein alpha-synuclein exists in a normal form, but for currently unknown reasons, the shape of the protein changes which causes it to clump together, forming a toxic aggregate that destroys neurons. One area of research is looking at how alpha-synuclein goes from a single protein with a normal shape to the destructive aggregates. Researchers are studying small molecules that stabilize the protein in its singular form to inhibit the aggregation.1