Parkinson's disease (PD) is a complex neurodegenerative pathology due to the loss of dopaminergic neurons in the human brain. The disease is characterized neuropathologically by the presence of Lewy bodies, which are toxic proteinaceous clumps composed mostly of aggregates of abnormally formed alpha-synuclein. An earlier study showed that exposing neurons to aggregated forms of alpha-synuclein leads to the development of pathological signs characteristic of PD. The aggregates in the pathological neurons can move to not only healthy neurons but also astrocytes, a type of cell with roles in neuron support and neuroimmunity.
However, little is known on the relations between the accumulation of these aggregates, their effects on astrocytes and their impact on the consequential neuronal lesions associated with the disease.
In a new study published in Cell Reports, the Neurodegenerative Diseases Laboratory's Protein Misfolding and Aggregation team (MIRCen) in partnership with a Lund University lab have brought to light a novel role for astrocytes in Parkinson's disease.
In their study, the researchers used skin biopsy samples from healthy people and patients with Parkinson's disease to generate induced pluripotent stem (iPS) cells, differentiated thereafter into astrocytes.
These latter were then put into contact with different types of alpha-synuclein aggregates or TNFα, a stress factor involved in neuroinflammation1 processes and progression in Parkinson's disease. The international team observed astrocytes reacting differently according to the stimulus. When exposed to alpha-synuclein aggregates, the cells took on an antigen presentation phenotype. The antigen presentation process involves the breakdown of the aggregates into smaller fragments that are transported to the cell surface for recognition by the immune system. In comparison, when exposed to TNF-α, the cells took on a pro-inflammatory phenotype.
Furthermore, when the astrocytes derived from patients with Parkinson's disease were exposed to alpha-synuclein, the researchers observed, contrary to what was theretofore believed, reductions in respiratory metabolism and the secretion of pro-inflammatory cytokines. The study's results suggest that the degeneration of dopaminergic neurons exposed to alpha-synuclein aggregates in Parkinson's disease is a consequence of reduced support from astrocytes.
Importantly, the research team also reported that their astrocytes were able to break down smaller aggregates, but not larger ones like those observed in the advanced stages of the disease. These results underline the importance of finding treatments that can act within the earliest possible therapeutic window for Parkinson's disease. Indeed, if the degenerative process is too advanced and the aggregates too large, the opportunity to break down the latter to reverse the former is lost.
The work offers a new point of view on the complex astrocytic immune response in Parkinson's disease and may enable the development of novel therapeutic approaches aimed at harnessing astrocytes to slow the progression of the disease.
1: In normal conditions, neuroinflammation is an immune mechanism to protect the brain from external aggressions and ensure homeostasis therein. Over the past few years however, researchers have suspected a role for it in certain neurodegenerative disease. Recent studies on postmortem brain tissue samples taken from patients with Parkinson's disease have pointed to neuroinflammation as a significant contributor to the neurodegenerative process, notably in the dopaminergic pathway between the substantia nigra and the striatum.