The key to assessing Alzheimer’s disease treatments? Test them in Parkinson’s disease patients.

David Dai was the lead author on this study, and was the writer of this brief. David is a MD/PhD student in Eddie Lee's lab. He is interested in understanding the mechanisms underlying neurodegenerative diseases.

or technically,

ADNC-RS, a clinical-genetic risk score, predicts Alzheimer’s pathology in autopsy-confirmed Parkinson’s disease and Dementia with Lewy bodies

[See Original Abstract on Pubmed]

Authors of the study: David L Dai, Thomas F Tropea, John L Robinson, Eunran Suh, Howard Hurtig, Daniel Weintraub, Vivianna Van Deerlin, Edward B Lee, John Q Trojanowski, Alice S Chen-Plotkin

In a world full of uncertainty, the only thing we can be sure of is that time will go on. And with time, unfortunately, comes disease. Age is the greatest risk factor for neurodegenerativebrain diseases characterized by the progressive loss of neurons over time. diseases which are characterized by the progressive loss of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Three of the most common neurodegenerativebrain diseases characterized by the progressive loss of neurons over time. diseases are AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, Parkinson’s disease, and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms.. Together they affect more than 6 million Americans, and that number is expected to reach over 9.8 million by 2030. To effectively diagnose and treat these diseases, it is vital to develop tools that can accurately predict who will develop disease. However, efforts to predict disease development, especially in AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, have largely been unsuccessful, despite advancements in our understanding of the genetic risk factors for AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease.

In all three diseases, abnormal proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregate, injure brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cells, and lead to neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles death, resulting in the symptoms that patients experience -- loss of memory, cognition, and movement. Doctors do their best to diagnose patients, but diagnoses are not confirmed until after patients die, when their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are autopsied, and the presence of abnormal proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates confirms which disease the patients experienced during life. In AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, these abnormal proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates are called amyloid-beta plaques (Aβ) and tau neurofibrillary tangles. In Parkinson’s disease and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms., these proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates are called Lewy bodies. Because of their similarities, Parkinson’s disease and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. are both included in a group of diseases called Lewy body diseases (LBD).

Although AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s and LBD are traditionally thought of as separate diseases, patients with LBD often have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. 50-80% of patients with a primary diagnosis of LBD also exhibit Aβ and tau proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates at autopsy-- hallmarks of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. Up to 40% of patients with a primary diagnosis of Parkinson’s have enough Aβ and tau aggregates in their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. for a secondary diagnosis of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. As only 10% of people age 65 and older have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease in the United States, it may not just be a coincidence that Parkinson’s patients commonly also have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. Patients with Parkinson’s or dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. may actually be at increased risk for developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease. This is important for clinicians to recognize when caring for LBD patients!

Taking advantage of LBD patients’ increased risk for developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks, David Dai and the Chen-Plotkin Lab at the University of Pennsylvania asked: Can we predict which Parkinson’s/dementia with Lewy Bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. patients are likely to develop AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks using known AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s genetic risk factors? They gathered various demographic and genetic variables that could impact AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s development and used a machine learning approach to identify the specific factors important for predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status.

They found that using only 4 pieces of information (age of onset and 3 pieces of genetic information), they could predict AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status to a modest degree. They transformed this information into a risk score, called the AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s Disease Neuropathological Change – Risk Score, that provides a continuous assessment of individuals’ risk for developing the hallmarks of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. A continuous risk score is useful because it reflects individuals’ incremental differences in disease development likelihood and allows researchers to set specific, numerical thresholds when predicting which patients are likely or unlikely to develop disease. They checked the effectiveness of their risk score in two additional groups and achieved comparable results. These additional validation steps were important because they showed that the risk score worked not only in the population that was used to build it but also in two other, unrelated groups. In other words, by showing that the risk score succeeded in three distinct groups, the researchers demonstrated that the AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s Disease Neuropathological Change -- Risk Score is a tool that could be successfully used in the general population.

These results have important scientific and clinical implications! By studying how the model made successful predictions, the scientists found that not all genetic information is equal when it comes to predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status in Parkinson’s/dementia with Lewy body patients. They identified three genetic locations that were particularly important for predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status in this group of individuals. They hope that further investigation will reveal why these locations are so crucial for the model’s predictions. If they are found to increase the development of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks in Parkinson’s and dementia with Lewy body patients, then treatments can be designed to block these genetic locations’ functions and maybe prevent AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease development in this subset of patients!

Given that the toxic proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates Aβ and tau accumulate in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. decades before patients develop symptoms, the medical community is trying to remove the aggregates as early as possible in the disease development process. However, this is extremely difficult because we don’t know who will develop AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s, and we don’t know if removing the aggregates even helps patients! This new risk score could help solve that problem. On average, patients receive clinical diagnoses of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s at ~80 years old, while Parkinson’s patients receive their diagnoses at ~60 years old. That means, using this risk score, we may be able to identify future AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s patients at least a decade before they develop symptoms, allowing us to first assess the effectiveness of Aβ and tau targeting treatments in a group of patients with increased risk of developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. If those treatments are proven to work, we may finally be able to slow the progression of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease!

Citations:

1. Alzheimer’s Association. 2020 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dement 2020;16(3):391+. You can find the report here.

2. Parkinson’s Foundation. Statistics. Parkinson’s Foundation. 2019 September 19. You can read the article here.

Want to learn more about developing a risk score to predict disease development? You can find the group’s full paper here!

Old genes: how the genetics of aging may play a role in Parkinson’s disease.

or technically,

Distinct cellular and molecular environments support aging-related DNA methylation changes in the substantia nigra.

[See Original Abstract on Pubmed]

Authors of the study: Maria Fasolino, Shuo Liu, Yinsheng Wang and Zhaolan Zhou

Have you ever wondered about the cause of Parkinson’s disease and what researchers are doing to improve treatment? First described in the 1800s, this devastating neurological disorder is currently estimated to affect seven to ten million people worldwide (with some of the more recognizable victims including Michael J. Fox, Muhammad Ali, and Robin Williams). Symptoms of the disease include motor dysfunction (shaking, rigidity, difficulty walking, etc), depression, and dementia. Although there are ways to slow disease progression, there is presently no cure available, and the average life expectancy is only 7-14 years after diagnosis. We still have a lot to learn about what makes certain people susceptible to the disorder and how we can improve treatment options. With this in mind, UPenn neuroscience graduate student Maria Fasolino and her team in the Zhou lab set out to learn more about what changes take place in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. during aging that might correlate to the development of Parkinson’s disease.

Doctors have known what the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of Parkinson’s disease patients look like for a long time. The disease causes brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cells (neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles) in the substantia nigra, which is a brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. area important for controlling movement, to die. Unfortunately, how this happens is still a mystery, and doctors aren’t sure why the substantia nigra is particularly susceptible. Scientists are taking a closer look at our DNA for more clues about the disease. The DNA inside each of our cells tells them what proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. to “print,” and you can think of proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. as the essential machinery of a cell executing its critical functions (enzymes, receptorsA protein on a cell’s surface that binds to specific molecules (i.e. other proteins or chemicals). Typically, a receptor is said to fit with its partner molecule(s) like a lock and key. When bound by the right molecule, receptors often transmit signals to the rest of the cell. and more). Your DNA is passed down from your parents, and scientists used to think that DNA did not change after being inherited (that is, the DNA you’re born with is the DNA you have for life). Over the last few decades, however, geneticists have realized that our DNA can actually be modified by our environment over the course of our lifetime. These chemical modifications to an individual’s DNA are referred to as epigenetics (epi=“on top of”; genetics=“genesA unit of DNA that encodes a protein and tells a cell how to function,” or DNA), and previous research has shown that epigenetic modification onto DNA accumulates over one’s lifetime, particularly in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Changes to DNA alter its ability to print proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies., and thus can drastically affect the function or survival of a cell. Maria’s main goal was to see if old age causes any epigenetic oddities in the substantia nigra (the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region implicated in Parkinson’s).

One of the many ways DNA can be modified is by a process known as methylation (a direct, chemical modification onto one of the building blocks of DNA). As mentioned above, DNA modifications such as methylation have the ability to affect how certain genesA unit of DNA that encodes a protein and tells a cell how to function are regulated and which proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. are made by a cell. Recently, researchers discovered that these modifications, such as methylation, aren’t as permanent as they thought. These ‘earmarks’ on our DNA can be kept, erased, or modified into a completely different type of modification, and this entire process can be quite dynamic throughout life!

Maria looked at aging mice to more closely study how the epigenetics of their substantia nigra cells may be changing over time. She found that the methylation marks on the DNA of these substantia nigra cells were much less stable with age when compared to a different brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. area not affected by Parkinson’s. Furthermore, she went on to show that this methylation difference is specific to dopamine neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, which are the cells in the substantia nigra implicated in Parkinson’s disease. It is not yet clear whether this different epigenetic pattern in the substantia nigra is what makes it particularly susceptible to cell death with aging. This epigenetic effect might be influenced by the presence of proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. that methylate DNA (DNMTs) or those that erase methylation (TETs), which could potentially serve as targets for treatment or early detection of the disease. Maria’s study provides us with more information about the cells in the substantia nigra and how they change with age, giving researchers novel insights on why Parkinson’s may specifically target this region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Millions of people worldwide suffer from Parkinson’s disease, but engineering treatments that target epigenetic marks like methylation could potentially stop Parkinson’s in it tracks.

About the brief writer: Dan Kalamarides

Dan is a third year student still amazed that we can record activity of a single, live neuron. He studies the role of inhibitory plasticity in the addictive properties of opioids and other drugs.

Interested in learning more about the epigenetics of aging? Take a look at Maria’s full paper here!

There's a new janitor in town: cleaning up the mess in ALS

or, technically, 
Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation [See the original abstract on PubMed]

Authors: Yvette C. Wong, Erika L.F. Holzbaur

Brief prepared by: Shachee Doshi and Patti Murphy
Brief approved by: Peter Dong
Section Chief: Shachee Doshi
Date posted: March 8, 2017 

Brief in Brief (TL;DR)

What do we know: Mitochondria are machines in our cells that produce energy. When mitochondria get damaged, healthy cells break down the damaged mitochondria and throw them away. In neurodegenerative diseases like ALS (Lou Gehrig's disease), damaged mitochondria inside neurons are not broken down, and this might be one way in which neurons die. 

What don’t we know: Why are damaged mitochondria not broken down inside neurons in people with neurodegenerative diseases? Can we find ways to help these people's neurons break down damaged mitochondria? 

What this study shows: A protein called optineurin helps cells break down damaged mitochondria. When there isn't enough optineurin or the optineurin is abnormal (like it is in some cases of ALS), damaged mitochondria are no longer broken down and build up in the neuron. 

What we can do in the future because of this study: We could design drugs to make optineurin even better at breaking down damaged mitochondria. These drugs would first be tested to see if they help animals with neurodegenerative diseases and then if they help humans with these diseases. 

Why you should care: Neurodegenerative diseases (Alzheimer's Disease, ALS, Frontotemporal Dementia) cause a lot of pain to patients and their families and cost a lot of money to society as a whole. Damaged mitochondria are found in neurons of patients in all these diseases. Finding ways to help cells break down damaged mitochondria can help us treat patients with these diseases.

Brief for Non-Neuroscientists

Mitochondria are the energy powerhouses of the cell. They make the fuel for all the cellular machinery to run smoothly. Accumulation of damaged and dysfunctional mitochondria has been observed in many neurodegenerative diseases, including ALS, Alzheimer's disease and Parkinson's disease. 

While it is unknown how mitochondria become damaged, it is known that accumulation of malfunctioning mitochondria is one of the factors contributing to neuronal cell death. Normally, a cell discards its damaged parts by a process known as autophagy. When it is mitochondria that are being discarded, this process is called mitophagy. 

One reason damaged mitochondria might build up in neurodegenerative diseases is defective mitophagy. If there were a way to rescue this defect, it could help cells get rid of these damaged mitochondria. This study identifies a pathway to do just that. The authors find that a protein called optineurin can be recruited to the mitochondria, which in turn leads to the recruitment of autophagosomes. Autophagosomes are special structures that envelop and engulf damaged cellular material to degrade it. If optineurin is removed from the cell, autophagosomes are no longer recruited to damaged mitochondria. Adding normal optineurin back into the cell can rescue autophagosome recruitment, but adding back an altered (mutated) form of optineurin that is found in ALS cannot rescue autophagosome recruitment. 

This study tells us that it may be possible to treat neurodegenerative diseases by increasing the amount of normal optineurin available in cells.

Brief for Neuroscientists

Mitochondrial dysfunction is a hallmark of many neurodegenerative diseases including ALS, frontotemporal dementia and Alzheimer's disease, and is implicated in disease pathophysiology. While mitophagy is a well-understood quality control mechanism that can degrade dysfunctional mitochondria, it seems to be compromised in these diseases. Optineurin is a protein that binds ubiquitin and the autophagosome via its LC3-binding domain, thus acting as an autophagy receptor. Mutations in optineurin have been found in familial cases of ALS. This paper describes a parkin-dependent role for optineurin in mitophagy in vitro. Using HeLa cells and confocal microscopy, the authors find that parkin is required to stabilize optineurin on the mitochondrial membrane, which in turn recruits the protein LC3 to initialize autophagosome formation. Depleting optineurin prevents autophagosome recruitment and mitochondrial turnover. This can be rescued by expressing wild type optineurin but not an ALS-linked mutant optineurin. Further, deleting autophagy receptor p62 did not prevent autophagosome formation, indicating a specific role for optineurin in initiating mitophagy. This study presents evidence for the contribution of mitochondrial dysfunction to cell death in neurodegeneration, and describes a mechanistic role for optineurin in mitophagy.