Three experts in the alpha-synuclein protein this month published a review of drug development against this target. Alpha-synuclein clumps into, scientists believe, toxic aggregates that damage cells in Parkinson's disease (PD). Preventing or breaking up those clumps may prevent, slow or stop PD progression.

Read more on the five alpha-synuclein therapies in clinical trials in our recent update.

Last week's paper, published in Experimental Neurology, is authored by Patrik Brundin, MD, PhD, of Van Andel Research Institute (VARI) in Michigan; Jeffrey Kordower, PhD, who holds a joint appointment at VARI and Rush University in Chicago; and Kuldip Dave, PhD, an on-staff scientist at The Michael J. Fox Foundation (MJFF).

They outline challenges facing the five current clinical trials with alpha-synuclein therapies and the many others on their heels. MJFF is leading various projects to answer key questions and accelerate treatments to stop PD.

• What molecular species of alpha-synuclein is the best target?
  It remains unclear what molecular species of alpha-synuclein is toxic. This protein is naturally disordered with extreme structural diversity, making it difficult to associate a particular species to toxicity. MJFF is bringing together a consortium of researchers and funding a large discovery initiative using different technologies to identify, replicate and validate specific molecular forms of alpha-synuclein. This knowledge would allow more specific targeting of the protein and development of tests to assess whether therapies are hitting the right types of alpha-synuclein to stop PD.

• How do we measure alpha-synuclein?
  An objective, biological measure (biomarker) of alpha-synuclein would help choose volunteers for trials and determine if a drug is effective. Since everyone with PD has alpha-synuclein aggregates -- right now only seen in autopsy -- the ability to image alpha-synuclein in the brain would be game-changing. MJFF has deployed significant resources to develop a tool to see this protein and announced a $2 million prize to the first team to do so. And in the absence of ability to directly visualize alpha-synuclein in the brain, the field has made tests to measure in more easily accessible fluids such as spinal fluid, blood and saliva. Read more on recent findings in this area and on a manual for best use of these tests.

• Can we stop disease before symptoms start?
  The underlying Parkinson's disease process begins several years, or even decades, before the development of motor symptoms. Some early non-motor symptoms (e.g., smell loss, constipation) may be caused by alpha-synuclein changes so targeting the protein in those early days of disease could slow progression. MJFF is studying people with symptoms associated with high risk of PD (smell loss and REM sleep behavior disorder) to measure alpha-synuclein at this stage.

Read more about alpha-synuclein.

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