When patients with Parkinson’s disease experience problems with coordination of voluntary movement and motor functions, it has traditionally been believed that this is due to the impact on a part of the brain called the substantia nigra. Through the production of a neurotransmitter called dopamine, this area is crucial for normal movement, and damage to it causes movement problems.

New insights into early neuronal damage in Parkinson’s Disease

However, a research team from DANDRITE and Aarhus University Hospital uncovered neuronal damage in another area of the brain that is closely related to movement issues and appears to be affected long before the disease reaches the substantia nigra. Their findings have recently been published in Acta Neuropathologica Communications.

“Parkinson’s disease is a complex disorder, and the underlying cause of movement symptoms likely arises from dysfunction across multiple populations of nerve cells in the brain. Our study draws attention to an area of the brain that is involved in the very early stages of the disease, and suggests that subtle decline in motor function could be present much earlier during the disease,” explains Asad Jan, Assistant Professor, DANDRITE alumni and study lead.

The nerve cells the researchers have focused on are called “gigantocellular neurons” and constitute an ancient motor circuit within a mesh of nerve cells known as the reticular formation. These nerve cells have widespread connections to several other neurons throughout the brain and spinal cord and play a role in the smooth execution of complex tasks related to movement and posture control, modulation of pain perception, and, according to some studies, sleep-wake circadian rhythms.

Parkinson's Disease might start in motor circuits outside substantia nigra
Using a mouse model, the researchers could track the progression of cellular processes linked to Parkinson’s disease from very early stages in the gigantocellular neurons and observe how they gradually affected the animals' motor skills and movement patterns. A progressive decline in the speed and extent of the animals' motor activity was quite striking:

“This is the first comprehensive study that provides a unique glimpse into the function of the gigantocellular neurons vis-à-vis features of movement disability in Parkinson’s disease, which tells us that Parkinson’s disease could start in motor circuits outside substania nigra,” Asad explains.

According to Asad Jan, this discovery is important for understanding the disease and for developing therapies because it shows that the disease has multiple stages, each requiring a specific type of treatment.

"For example, damage to the motor circuits involving the gigantocellular nerve cells or their connections may underlie some subtypes of Parkinson’s disease, which do not respond to dopamine replacement therapies used in the clinic," explains Asad and continues:

“With further improvements, we hope that this model hold promise for novel discoveries and could serve as a testbed for new potential treatment options for (at least some subtypes of) Parkinson’s patients.”
 

Facts about the study:

• For more information about the research:
  Asad Jan, ajan@aias.au.dk; +45 51 89 22 46
• Facts about study type:
  Basic research involving animal models approved by the Danish Dyreforsøgstilsynet
• Collaborators from home and abroad:
  Poul Henning Jensen (DANDRITE), Marina Romero-Ramos (AU), Wilma van de Berg (UMC Amsterdam)
• External funding:
  Michael J. Fox Foundation (Project grant to AJ)
• Information on any impartiality issues:
  No competing interests to declare
• Information on deviations from the principle that the research result is based on a peer-reviewed article published in a scientific journal:
  The results have been published after peer-review at the Acta Neuropathologica Communications
• Direct link to the abstract or the scientific article: https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-025-01948-7