Insight into Parkinson’s 2020, Day 1, part 1 – Conference notes

Insight into Parkinson’s 2020, Day 1, part 1 – Conference notes

Insight 2020 is the largest online conference for people with Parkinson’s disease (PD), their caregivers, and those who work with the PD community. It took place this year on April 1-3, and covered a wide range of topics, from living positively to the latest PD research. We at Stanford Parkinson’s Community Outreach attended all three days of the virtual conference and took notes on some of the talks that seemed most interesting or relevant to our audience. Highlights from Day 1 of the conference are below. Due to length, we broke up the blog post into two parts for each day of the conference. This is Part 1 of the Day 1 summary.

To see the agenda for the full conference, visit the Insight 2020 event website here.

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A basic science approach to understanding PD

Speaker: Prof. Randy Schekman, UC Berkeley

Insight into Parkinson’s Conference, April 1, 2020

Notes by Lauren Stroshane, Stanford Parkinson’s Community Outreach

Nobel Laureate Prof. Randy Schekman characterized PD as a pandemic unto itself, as new diagnoses of PD continue to increase steeply. By the year 2040, it is estimated that 17.5 million people worldwide will have PD. China is affected most seriously, accounting for approximately half of PD cases globally. The disease probably has multiple origins. It also progresses quite differently in different people, yet we treat it as a single disease. There are patients whose PD progresses more rapidly, resulting in early disability and dementia, while others progress slowly, experiencing minimal disability or cognitive changes.

The drug industry has often attempted to find new therapies for PD but these studies often fail, perhaps in part because all PD is not the same. It may be that some drugs would work well for certain “types” of PD and not others, but we do not yet have the ability to distinguish between subtypes in this diverse disease.

The speaker touched on some of the basic science underlying PD and Lewy body disease. Frederick Lewy first described an accumulation of abnormal proteins within brain cells (neurons) in 1912, calling them Lewy bodies. These brain cells produce the neurotransmitter dopamine, a chemical messenger vital to our brain’s function, and are called dopaminergic neurons. In PD, these neurons gradually die off, leading to a deficiency of dopamine in the brain. We now know that Lewy bodies are made up of a specific protein, alpha-synuclein, which is found not only in brain tissue but in other areas throughout the body as well.

A scientific theory called the Braak hypothesis posits that Lewy bodies may originate in the gut, gradually traveling up to the brain via the vagus nerve and disseminating from the brainstem slowly out to the rest of the brain. However, research into this theory is hampered by our current inability to “see” or detect these Lewy bodies until after a patient has died, by studying the brain tissue itself.

There are approximately 86 billion neurons in your brain. Each neuron has root-like projections that make up to 10,000 connections with other nerve cells, forming up to a trillion different of connections that make up our thoughts, memories, and functions.

Within a generic human cell is a nucleus, the center of a cell that contains its genetic material, as well as various tiny organs throughout the cell called organelles, which produce various functions within the cell. Lysosomes are the garbage collectors, for instance, while mitochondria are the power generators for the cell. There are numerous diseases that affect human mitochondria, which contain their own genetic material in addition to that of the cell at large.

If a mitochondrion is damaged, a lysosome should ordinarily engulf or swallow it to keep the rest of the mitochondria healthy. In some forms of PD that are caused by genetic mutations (PINK1 and Parkin genes), this process is disrupted: the damaged mitochondria are not recognized and persist in the cell, causing a big mess. Sometimes the damaged mitochondria break, spilling their own genetic code into the rest of the cell (the cytoplasm) and triggering the cell to respond with an inflammatory response that puts the whole cell in peril. This can cause early cell death such as that seen in dopaminergic neurons in certain genetic forms of PD. Other genetic mutations associated with PD operate differently.

Aligning Science Across Parkinson’s (ASAP) is an organization that is trying to create a roadmap for future PD research, to address critical gaps in our scientific understanding of the disease. ASAP was started by the Sergey Brin Family Foundation after his father’s diagnosis with PD. Prof. Schekman became involved due to his late wife’s PD. The goal of ASAP’s efforts are to provide strategies and mechanisms for directing resources toward scientific research to answer key questions that remain about PD.

Prof. Schekman shared a quote from Prof. Dario Alessi with the University of Dundee, Scotland:

“… There isn’t a lot of funding to do the fundamental research on one gene or one protein that would be needed to really understand these things… Funding bodies want us to solve diseases and work with companies to figure out shortcuts that can be made into a drug. But we don’t have the fundamental basis that is needed to really solve these problems.”

He urged us to think of PD as a kind of highly complex puzzle, involving many different biological systems:

  • Calcium homeostasis
  • Mitochondrial dysfunction
  • Apoptosis
  • Synaptic pathobiology
  • Failure of protein degradation
  • Alpha-synuclein misfolding
  • Neuroinflammation
  • Unknown pathways

The task of basic science is to label and understand each of these different puzzle pieces, then figure out how to fit them all together to gain a better understanding of PD as a whole.

Prof. Schekman proposes a 4-pronged approach to scientific focus on PD:

  1. Genetics and associated biology: Determining what mechanisms are triggered by genetic mutations that are associated with PD.
  2. Neuroimmunology: Gaining a better understanding of the role of inflammation and immune function in PD.
  3. Circuitry: Studying the circuits in the nervous system that go awry in PD pathology. We do not yet have a map of all the thousands of connections that dopaminergic neurons make within the brain.
  4. PD prodrome: Understanding how these elements play into the lengthy prodrome, or period of years to decades when non-motor PD symptoms (such as sleep issues, or lost sense of smell) start to occur, before overt motor symptoms of PD are observed.

ASAP has begun this effort and is identifying scientific teams that can collaborate to solve these questions; attracting diverse talent from fields outside of PD and neuroscience who may contribute fresh ideas; and fostering the values of collaboration and transparency in order to accelerate the ability of researchers to gain useful, reproducible scientific insights.