Fight Aging!

Today I'll point out a couple of recently published research results that add to the understanding of Parkinson's disease and its progression. Parkinson's disease is comparatively straightforward as neurodegenerative diseases go - which is to say that its biochemistry is still enormously complex in detail, but it hasn't proven as hard to identify the important aspects as is the case for Alzheimer's disease. At root, this is a synucleinopathy, a condition caused by the accumulation of α-synuclein deposits. This results in mitochondrial dysfunction and cell death in a small but important population of dopamine-generating neurons connected to motor function, but also a more widespread disruption of normal function in the brain. The challenge in Parkinson's is less a matter of knowing where to intervene, meaning the targeted removal of α-synuclein, but rather the construction of an effective methodology. You might look at one of the SENS Research Foundation reviews on the topic to get a sense of just how difficult it is to safely clear a specific form of metabolic waste from the brain.

Why do only some people develop Parkinson's disease? In a small number of cases, it is due to mutated genes, particularly those like parkin that are important in the processes of cellular maintenance. Impairment of autophagy directed at quality control of mitochondria appears to be an important facet of Parkinson's disease, but in those patients without evidence of mutation, the path to Parkinson's may be a random one of small differences in age-related damage and declining cellular maintenance that snowball and accelerate over time. A little less removal of metabolic waste leads to a little more α-synuclein and a little more mitochondrial dysfunction, which in turn further impacts maintenance systems, and so the feedback loop progresses, ever faster over time. Given enough time, everyone would suffer Parkinson's disease eventually - but as things stand, other processes of aging kill most people before that can happen.

Beyond clearance of α-synuclein, cell therapy is the other major area of effort in the production of therapies for Parkinson's disease. The goal there is to replace lost dopamine-generating neurons with new cells capable of taking over the same function in the brain. Since the process of loss is gradual, this should provide lasting benefit, even though it doesn't address the causes of cell loss - the new cells will be destroyed in time, just like the old ones. This situation is similar in near any proposed use of cell replacement therapy in older individuals: the tissue environment is typically hostile and damaged, and the details of how and why existing cell populations are no longer working matter greatly when it comes to the potential effectiveness of introducing new cells. Will they function correctly at all, or will they quickly succumb?

Researchers uncover culprit in Parkinson's brain cell die-off

If we could peer into the brains of Parkinson's patients, we'd see two hallmarks of the disease. First, we'd see a die-off of the brain cells that produce a chemical called dopamine. We'd also see protein clumps called Lewy bodies inside the neurons. Researchers believe a key to treating Parkinson's is to study possible links between these two phenomena. "This study identifies the missing link between Lewy bodies and the type of damage that's been observed in neurons affected by Parkinson's. Parkinson's is a disorder of the mitochondria, and we discovered how Lewy bodies are releasing a partial break-down product that has a high tropism for the mitochondria and destroys their ability to produce energy."

Lewy bodies were described a century ago, but it was not until 1997 that scientists discovered they were made of clumps of a misfolded protein called α-synuclein. When it's not misfolded, α-synuclein is believed to carry out functions related to the transmission of signals between neurons. Researchers looked at cell cultures of neurons that were induced to accumulate fibrils made of misfolded α-synuclein, mimicking Lewy bodies in patients with Parkinson's. They discovered that when α-synuclein fibrils are broken down, it often creates a smaller protein clump, which they named pα-syn* (pronounced "P-alpha-syn-star").

It turns out that the result of that partial degradation, pα-syn*, is toxic. Researchers made this discovery by labeling the pα-syn* with an antibody so they could follow it throughout the cell after it was created. They observed that pα-syn* traveled and attached itself to the mitochondria. Further investigation revealed that once the pα-syn* attached, the mitochondria started to break down. These fragmented mitochondria lose their ability to carry an electrochemical signal and produce energy. "The Lewy bodies are big aggregates and they're sitting in the cell, but they don't come into direct contact with the mitochondria in the way pα-syn* does. With this discovery, we've made a direct connection between the protein α-synuclein and the downstream effects that are observed when brain cells become damaged in Parkinson's."

Study Uncovers New Insights Into Cause of Cell Death in Parkinson's

Researchers have found that cardiolipin, a molecule inside nerve cells, helps ensure that a protein called alpha-synuclein folds properly. Misfolding of this protein leads to protein deposits that are the hallmark of Parkinson's disease. These deposits are toxic to nerve cells that control voluntary movement. When too many of these deposits accumulate, nerve cells die. "Identifying the crucial role cardiolipin plays in keeping these proteins functional means cardiolipin may represent a new target for development of therapies against Parkinson's disease."

The study revealed that inside cells, alpha-synuclein binds to mitochondria, where cardiolipin resides. Cells use mitochondria to generate energy and drive metabolism. Normally, cardiolipin in mitochondria pulls synuclein out of toxic protein deposits and refolds it into a non-toxic shape. The researchers found that in people with Parkinson's disease, this process is overwhelmed over time and mitochondria are ultimately destroyed. Understanding cardiolipin's role in protein refolding may help in creating a drug or therapy to slow progression of the disease.