All roads to Parkinson’s disease lead to the nigrosome

The path to Parkinson's disease!

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The degeneration of dopaminergic neurons in the ventral tier of the substantia nigra pars compacta (SNc) is a prominent feature of Parkinson’s disease (PD), while those in the dorsal tier and ventral tegmental area are relatively unaffected. The selective vulnerability of dopaminergic neurons in Parkinson’s disease (PD) has been a longstanding puzzle in neuroscientific research.

It has been shown that neuroinflammation and immune cell infiltration play a crucial role in the neurodegeneration in PD. Nevertheless, the connection between the vulnerability of selective dopaminergic neurons, the response of glial and immune cells, and vascularization, as well as their interactions, remains to be understood.

The recent study published in npj Parkinson’s Disease by the Centro Integral de Neurociencias HM Cinac has shed light on the unique characteristics of the ventral tier of the substantia nigra pars compacta, known as the nigrosome.

The researchers investigated how glial cell activation and immune cell infiltration contribute to the vulnerability of ventral dopaminergic neurons in the midbrain in a non-human primate model of PD. They also assessed the structural characteristics of the vasculature in specific midbrain regions.

The study found significant microglial and astroglial activation in the entire midbrain of Parkinsonian monkeys, with no major differences observed in sub-regions.

Surprisingly, the ventral substantia nigra showed a higher level of vascularity compared to other areas. This characteristic could potentially make this region more prone to immune cell infiltration under abnormal conditions, as there was a greater presence of both T- and B- lymphocytes in Parkinsonian monkeys.

The increased vascular density in the ventral region of the SNc could be a relevant factor in the differing vulnerability of dopaminergic neurons in the midbrain. The increased infiltration of T- and B- cells in this region, in addition to other substances or poisons, might also play a role in making dopaminergic neurons more vulnerable in PD.

“Imagine the midbrain as a bustling city with various neighborhoods, each with its own network of roads and pathways. In this cityscape, the nigrosome is like a central hub with an intricate network of highways and streets. This network ensures efficient delivery of necessary supplies under normal conditions, much like a well-functioning city intersection”, explains Dr. Tiziano Balzano, the first author of the paper.

“However, under pathological conditions, this dense network of blood vessels can become a double-edged sword. The same highways that facilitate efficient supply routes also make the nigrosome an easy target for harmful elements like toxins and immune cells, including lymphocytes. It’s as if this busy intersection becomes prone to traffic jams and blockages during an influx of unwanted traffic,” he continues.

“Our observations in parkinsonian animals confirmed this metaphor. We saw that lymphocytes preferentially flood into the nigrosome while other parts of the midbrain remain relatively unaffected. This is comparable to a critical city crossroads that, while essential, also becomes a vulnerable point for incoming threats. The unique exposure and susceptibility of the nigrosome highlight its critical role and vulnerability in the context of Parkinson’s disease,” he concludes.

These findings outline a groundbreaking proposal on how specific mechanisms, such as neuroinflammation and immune cell infiltration, can significantly impact a specific region, largely due to its unique vascular cytoarchitecture. By employing immunosuppressive drugs to reduce immune cell activation or entry or by addressing the detrimental effects of peripheral immune activity in this region, clinicians may potentially achieve a significant breakthrough in slowing or halting the progression of the disease from the periphery to the CNS.

Journal reference:

  1. Tiziano Balzano, Natalia López-González del Rey, Noelia Esteban-García, Alejandro Reinares-Sebastián, José A. Pineda-Pardo, Inés Trigo-Damas, José A. Obeso & Javier Blesa. Neurovascular and immune factors of vulnerability of substantia nigra dopaminergic neurons in non-human primates. npj Parkinson’s Disease, 2024; DOI: 10.1038/s41531-024-00735-w
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