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The immune system starts neuronal degeneration in Parkinson's disease


The death of dopaminergic neurons in the substantia nigra is a typical hallmark of Parkinson's disease (PD). The loss of dopamine in the main target area of these neurons, the striatum, is accompanied by motor deficits, including a lack of movement (bradykinesia) and a resting tremor. Currently, there are no disease-modifying therapies to prevent progression of PD, whose neuropathologic hallmarks are intraneuronal accumulations of α-synuclein and mitochondrial dysfunction.


In addition to mutations in α-synuclein, alterations in genes encoding proteins such as an E3 ubiquitin ligase (parkin) play a role. This enzyme is critically involved in mitochondrial quality control (damaged mitochondria release reactive oxygen species). A recently published study now presents evidence for a novel signaling mechanism in dopaminergic neurons that leads to activation of the so-called NLRP3 inflammasome in cells with parkin mutations. The inflammasome is an important component of the innate immune system that consists of the cytosolic pattern recognition receptor NLRP3, the adaptor protein ASC, and caspase-1.


The NLRP3 inflammasome responds primarily to irritants rather than pathogens, thus causing 'sterile' and chronic inflammations. The complex forms only when macrophages, microglia, or neurons detect danger signals (e.g., asbestos or other pollutants). The subsequently activated caspase-1 then produces mature interleukin-1β and cleaves gasdermin, a protein that forms pores in the cell membrane and allows cytokines to leak out (this cell death mechanism is also called pyroptosis). Such an inflammatory response appears to be a key contributor to Parkinson's pathology and is associated with the loss of functional parkin.


In their work, the authors were able to show that the loss of functional parkin in dopaminergic neurons leads to an increase in active NLRP3 inflammasomes, resulting in neuronal degeneration in animal models of Parkinson's disease (in so-called conditional parkin knockouts and α-synuclein fibril mice). A particularly relevant finding from a therapeutic perspective was that neuronal degeneration was no longer observed after NLRP3 was knocked out.


In addition, Ted and Valina Dawson's group demonstrated that NLRP3 is a Parkin substrate and that Parkin normally inhibits inflammasome priming (signal-1) by ubiquitinating NLRP3 and priming it for proteasomal degradation. Loss of Parkin function contributes critically to the activation of the NLRP3 complex (termed Signal-2) via the accumulation of a Parkin-interacting substrate (PARIS). This leads to the formation of mitochondrial oxygen free radicals (MitoROS, see Figure).


Fig. Loss of parkin in neurons triggers activation of the NLRP3 inflammasome and the

subsequent neurodegeneration in animal models of Parkinson's disease. Genetic mutations or toxic a-synuclein can lead to loss of functional parkin in dopaminergic neurons of the substantia nigra. PARIS and NLRP3 are parkin substrates that are normally targeted for proteasomal degradation but accumulate in the absence of parkin. Inflammasome formation in neurons contributes to neurodegeneration in models of Parkinson's disease (Fig. 1 from Zengeler KE, Lukens JR, 2022, Taking the parkin brakes off of neuronal NLRP3 drives inflammasome activation and neurodegeneration in Parkinson's disease. Neuron 110:2356).


The authors further examined neurons derived from Parkinson's disease patients or from control subjects and found similar signs of neuronal inflammasome activation in the absence of parkin, i.e., oligomerization of the above ASC, cleaved caspase-1, and increased NLRP3 levels. Finally, they also examined human tissues from Parkinson's disease patients, which showed the same signs of inflammasome activation in dopaminergic neurons.


In conclusion, novel therapeutic strategies aimed at inhibiting NLRP3 inflammasome activation by maintaining parkin activity represent promising approaches for the treatment of Parkinsons's disease. However, it is also possible that inflammasome-mediated cell death is only one of several causes of neurodegeneration in PD. In this case, blocking the inflammasome alone might not be sufficient to prevent neuronal cell death once the disease has progressed.


References:


Panicker N, Kam T-I, Wang H, ..., Dawson VL, Dawson TM (2022) Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease. Neuron 110:2422


Zengeler KE, Lukens JR (2022) Taking the parkin brakes off of neuronal NLRP3 drives inflammasome activation and neurodegeneration in Parkinson's disease. Neuron 110:2356


Image credit: iStock/Dr_Microbe


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