Conventionally neurodegenerative diseases are characterized by unique hallmark pathological features. Traditionally Parkinson’s disease is described as a synucleinopathy, a disease characterized by the accumulation and aggregation of the protein α-synuclein. This pathological α-synuclein is often modified by processes such as phosphorylation and can accumulate in structures known as Lewy bodies or Lewy neurites. Alzheimer’s disease (AD) is commonly associated with neurofibrillary tangles made of tau protein as well as amyloid plaques made of β-amyloid, and Amyotrophic Lateral Sclerosis (ALS) is associated with TDP-43 aggregates. However, it has recently been shown that these hallmark pathological features only tell part of the story, and that most (>90%) of individuals suffering from neurodegenerative diseases actually have pathological forms of more than one of these proteins within their brains. While extremely common, the role of these co-pathologies is still very poorly understood.

PD patients on average present with three co-pathologies, particularly those patients that are cognitively impaired. In addition to α-synuclein, recent reports suggest that about half of PD patients have tau pathology, 80% of PD patients have β-amyloid pathology and 7% of PD patients have TDP-43 pathology. While the role that these co-pathologies play in the disease process is still unclear, there is evidence in animal models that the addition of co-pathologies may worsen disease progression.

The presence of multiple co-pathologies could suggest that either one type of pathology initiates a disease cascade leading to the aggregation of additional proteins, or that there is a disease associated environment which leads to aggregation of multiple proteins. There is evidence for each of these potential mechanisms suggesting that both may be at play. Alpha synuclein has been shown to mediate tau phosphorylation, and reduction of tau in mouse models of mutant α-synuclein has been shown to reduce memory deficits. Additionally, there is genetic evidence for a role of tau in PD as the H1 haplotype of the gene encoding the tau protein is linked to increased risk of developing PD. Pathological tau has been identified not just in the brains of PD patients, but also in individuals with mild motor deficits, and, along with α-synuclein, even in grafted neurons.

Studies suggest a correlation between β-amyloid and motor and cognitive impairment in PD patients, and it has been proposed that the high rate of sleep disturbance in PD patients may play a role in β-amyloid deposition, as it is thought to normally be cleared from the brain during sleep. The potential role of TDP-43 pathology is less clear, though it was shown that increasing the amount of TDP-43 in the brain of rats resulted in loss of dopaminergic neurons.

There are also a number of common disease mechanisms at play in PD that also occur in other neurodegenerative diseases such as AD and ALS. These shared disease mechanisms may create an environment in which multiple disease associated proteins aggregate. Mitochondrial dysfunction, lysosomal dysfunction and neuroinflammation are all known to occur in most neurodegenerative diseases and may result in a cellular environment which favors aggregation of many different proteins. Chronic neuroinflammation is another hallmark of PD and has been identified both in postmortem human brains, and in animal models. Activation of glial cells such as microglia and astrocytes, is common, along with expression and release of pro-inflammatory factors. Aggregated α-synuclein has been shown to increase neuroinflammation, and at the same time, there is also evidence that inflammation is able to promote α-synuclein aggregation.

The scientific community is increasingly recognizing the complexity of neurodegenerative diseases such as Parkinson’s disease. One of these layers of complexity is the presence of multiple pathological features or co-pathologies. Understanding the role of these co-pathologies is vital for both treatment decisions and the development of new therapeutics. As precision medicine becomes a reality it is extremely important to consider that a patient may be suffering from multiple pathologic processes and that a treatment targeted against a single protein may be insufficient to slow or stop disease. This new understanding also suggests a potential role for the use for treatments targeting proteins traditionally associated with AD such as β-amyloid and tau in PD. New therapeutics need to be designed with this new understanding of disease pathogenesis in mind, focusing on strategies that target either co-pathologies, or the disease associated environment.

Jeffrey H. Kordower, PhD is the director at the ASU-Banner Neurodegenerative Disease Research Center Biodesign Institute Arizona State University. He has presented at many previous WPC congresses, starting back at the 1st World Parkinson Congress in 2006. He is now a member of the  WPC Board of Directors.

Ideas and opinions expressed in this post reflect that of the author solely. They do not necessarily reflect the opinion(s) or position(s) of the World Parkinson Coalition®