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Brain gene expression profiles in Parkinson’s disease biased by altered cell composition

A new study at the Department of Clinical Medicine and Haukeland University Hospital unfolds important new knowledge about altered gene regulation in Parkinson’s disease.

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Parkinson’s disease affects more than 10 million people worldwide. It causes a combination of debilitating symptoms, including uncontrollable shaking and other abnormal movements, loss of balance, low blood pressure, bladder and intestinal problems, sleeping disorders and dementia. In spite more than 200 years of research, the causes of Parkinson’s disease remain largely unknown and no effective treatments exist to slow down disease progression

Studying gene expression in the brain provides important insight into the mechanisms underlying Parkinson’s disease. According to a recently published study at NeuroSys-Med and Department of Clinical Medicine, however, this type of analysis is also particularly prone to bias, caused by underlying differences in cell-type composition between healthy individuals and people with Parkinson’s disease.

Applies also to Alzheimer’s and other neurodegenerative diseases

Neuronal cells tend to die and disappear in people with Parkinson’s disease, while supporting cells (also known as glia) remain unchanged, or increase in numbers, in some areas of the brain.

Thus, the expression levels of genes that are normally highly expressed in neuronal cells may appear decreased in Parkinson’s disease, whereas those that are expressed in supporting cells may appear increased.

"Accounting for this phenomenon is crucial in order to unveil molecular processes linked to the disease", the researchers write in a press release.

A similar challenge applies to other common neurodegenerative diseases, such as Alzheimer's, amyotrophic lateral sclerosis (ALS) and Huntington's disease.

Proposing a new framework

The research team from Bergen proposed a framework for analyzing gene expression in the brain while accounting for changes in the underlying cell composition. To this end, the authors looked at the expression level of known genes that are specific to each brain cell type, and estimated relative cellular composition for each sample. This variation in cellular composition was then accounted for when measuring the differences between Parkinson's disease brain and healthy controls.

"Our results demonstrate that differential gene expression signatures in Parkinson’s brain are strongly associated with underlying differences in cell type composition. Modeling cell type heterogeneity is crucial in order to disentangle the underlying disease mechanisms in the Parkinson’s disease brain, and in other neurodegenerative diseases."

Gonzalo Nido, the first author of the study, sais: "Previous studies of gene expression in the brain of individuals with Parkinson's disease have looked at global differences between tissues that may be radically different in terms of cellular composition. These differences need to be accounted for when investigating the gene expression signatures associated with the disease. Modeling cell type heterogeneity is crucial in order to disentangle the underlying disease mechanisms in neurodegenerative diseases".

Corresponding author:

Charalampos Tzoulis, MD, PhD
Professor of Neurology and Neurodegeneration
Head, Neuromics Research Group
Director for Neurodegeneration & Vice Center Director, Neuro-SysMed: Center of Excellence for Clinical Research in Neurological DiseasesDepartment of Neurology, Haukeland University Hospital
Department of Clinical Medicine, University of Bergen

Research article:

The study was conducted by the research group of Prof. Charalampos Tzoulis at the University of Bergen and Haukeland University Hospital, Norway. The paper’s first author Dr Gonzalo S Nido is a Postdoctoral Fellow in Tzoulis’ laboratory. The findings were published in the open access journal Acta Neuropathologica Communications:


DOI: 10.1186/s40478-020-00932-7