How alpha-synuclein affects brain cell communication: APDA-funded research published

In a recently published study, Dr. Gary Ho, a recipient of APDA’s most prestigious George C. Cotzias grant, studied the role of alpha-synuclein in the formation and recycling of synaptic vesicles, the system that allows nerves to talk to each other.

Abnormally aggregated alpha-synuclein is a main component of the Lewy body which is the pathologic hallmark of Parkinson’s disease (PD). However, alpha-synuclein is normally present in the brain and deciphering its various and complex roles is a key research strategy to understanding what goes wrong in PD.

One possible function of alpha-synuclein is in the regulation of synaptic vesicles, the cell’s transport containers that move signaling chemicals from one neuron to the next. This process allows for nerves to communicate across the synapse, the space that exists between neurons.

To investigate this potential key function, Dr. Ho used a system that he developed for measuring the recycling and release of signaling chemicals from synaptic vesicles. He started with iPSCs, induced pluripotent stem cells, from several sources, including those that were derived from a skin biopsy of a person with PD who harbored a genetic mutation that caused too much alpha-synuclein to be produced. Dr. Ho then differentiated the iPSCs into cortical nerve cells.

Dr. Ho utilized these nerve cells in his novel system to see if they were able to recycle synaptic vesicles and release signaling chemicals as efficiently as nerve cells without the overabundance of alpha-synuclein. He showed that too much alpha-synuclein reduced synaptic vesicle cycling, impacting the interaction between nerves. This impaired communication could be a core feature of PD pathology and finding ways to normalize this could play a role in treatment of PD.

APDA is thrilled to be funding Dr. Ho’s work.

Dr. Ho said “I am tremendously grateful for the support of APDA, which made this work possible. Our findings shed light on how alpha-synuclein, a critical protein in PD, directly affects how brain cells communicate. This is an important step in understanding how different PD symptoms arise at a cellular level, in particular cognitive dysfunction. In supporting this and other research, the APDA is contributing meaningfully to our collective efforts in finding new treatments to slow the progression of PD.”

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