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Similar neuronal imprint and no cross-seeded fibrils in α-synuclein aggregates from MSA and Parkinson's disease.

ABSTRACT: Aggregated alpha-synuclein (α-syn) is a principal constituent of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) observed respectively inside neurons in Parkinson's disease (PD) and oligodendrocytes in multiple system atrophy (MSA). Yet, the cellular origin, the pathophysiological role, and the mechanism of formation of these inclusions bodies (IBs) remain to be elucidated. It has recently been proposed that α-syn IBs eventually cause the demise of the host cell by virtue of the cumulative sequestration of partner proteins and organelles. In particular, the hypothesis of a local cross-seeding of other fibrillization-prone proteins like tau or TDP-43 has also been put forward. We submitted sarkosyl-insoluble extracts of post-mortem brain tissue from PD, MSA and control subjects to a comparative proteomic analysis to address these points. Our studies indicate that: (i) α-syn is by far the most enriched protein in PD and MSA extracts compared to controls; (ii) PD and MSA extracts share a striking overlap of their sarkosyl-insoluble proteomes, consisting of a vast majority of mitochondrial and neuronal synaptic proteins, and (iii) other fibrillization-prone protein candidates possibly cross-seeded by α-syn are neither found in PD nor MSA extracts. Thus, our results (i) support the idea that pre-assembled building blocks originating in neurons serve to the formation of GCIs in MSA, (ii) show no sign of amyloid cross-seeding in either synucleinopathy, and (iii) point to the sequestration of mitochondria and of neuronal synaptic components in both LBs and GCIs.

SUBMITTER: Laferriere F

PROVIDER: S-EPMC8758785 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Parkinson's disease is characterized by degeneration of substantia nigra dopamine neurons and by intraneuronal aggregates, primarily composed of misfolded α-synuclein. The α-synuclein aggregates in Parkinson's patients are suggested to first appear in the olfactory bulb and enteric nerves and then propagate, following a stereotypic pattern, via neural pathways to numerous regions across the brain. We recently demonstrated that after injection of either mouse or human α-synuclein fibrils into the olfactory bulb of wild-type mice, α-synuclein fibrils recruited endogenous α-synuclein into pathological aggregates that spread transneuronally to over 40 other brain regions and subregions, over 12 months. We previously reported the progressive spreading of α-synuclein aggregates, between 1 and 12 months following α-synuclein fibril injections, and now report how far the pathology has spread 18- and 23-month post-injection in this model. Our data show that between 12 and 18 months, there is a further increase in the number of brain regions exhibiting pathology after human, and to a lesser extent mouse, α-synuclein fibril injections. At both 18 and 23 months after injection of mouse and human α-synuclein fibrils, we observed a reduction in the density of α-synuclein aggregates in some brain regions compared to others at 12 months. At 23 months, no additional brain regions exhibited α-synuclein aggregates compared to earlier time points. In addition, we also demonstrate that the induced α-synucleinopathy triggered a significant early neuron loss in the anterior olfactory nucleus. By contrast, there was no loss of mitral neurons in the olfactory bulb, even at 18 month post-injection. We speculate that the lack of continued progression of α-synuclein pathology is due to compromise of the neural circuitry, consequential to neuron loss and possibly to the activation of proteolytic mechanisms in resilient neurons of wild-type mice that counterbalances the spread and seeding by degrading pathogenic α-synuclein.

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Similar neuronal imprint and no cross-seeded fibrils in α-synuclein aggregates from MSA and Parkinson's disease.

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