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Contrasting Pathological Versus Normal Alpha-synuclein Assemblies

Study Rationale:                   
Parkinson’s disease (PD) is characterized by Lewy bodies composed of the protein alpha-synuclein in dopamine-producing nerve cells. The protein aggregates are also seen in the brains of people with dementia with Lewy bodies (DLB), a similar condition marked by earlier cognitive impairment. We seek to isolate and identify the abnormal forms of alpha-synuclein that accumulate in the brains of people with PD or DLB.

We hypothesize that a bundle of four alpha-synuclein proteins called a tetramer unravels to yield single copies of alpha-synuclein that then misfold to form the Lewy bodies seen in PD and DLB.

Study Design:
We will use biochemical methods to isolate normal forms of alpha-synuclein (including the tetramers) from control human brain tissue and abnormal forms from PD and DLB brain tissue. We will compare their properties and biological activities in certain tests of nerve cell toxicity.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
This close comparison of alpha-synculein may allow us to find treatments to prevent the conversion of the normal protein into the abnormal forms. Quantifying the abnormal form might also be an aid to diagnosing PD or DLB.

Next Steps for Development:
The next big steps will be 1) to measure the ratio of abnormal to normal forms of alpha-synuclein in biological fluids (spinal fluid, blood) and 2) to devise a “drug screen” to find compounds that help restore the alpha-synuclein ratio to normal.


  • Dennis J. Selkoe, MD

    Boston, MA United States

  • Bradley Hyman, MD

    Boston, MA United States

  • Thomas Pochapsky, PhD

    Boston, MA United States

  • Clemens Scherzer, MD

    Boston, MA United States

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