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Pathological ?-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.

ABSTRACT: Parkinson's disease is characterized by abundant ?-synuclein (?-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic ?-Syn fibrils led to the cell-to-cell transmission of pathologic ?-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic ?-Syn and the cardinal features of Parkinson's disease.

SUBMITTER: Luk KC

PROVIDER: S-EPMC3552321 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.

Luk Kelvin C KC Kehm Victoria V Carroll Jenna J Zhang Bin B O'Brien Patrick P Trojanowski John Q JQ Lee Virginia M-Y VM

Science (New York, N.Y.) 20121101 6109

Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy patholog ...[more]

PMID: 23161999

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Project description:BackgroundThe accumulation of misfolded proteins appears as a fundamental pathogenic process in human neurodegenerative diseases. In the case of synucleinopathies such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB), the intraneuronal deposition of aggregated alpha-synuclein (?S) is a major characteristic of the disease, but the molecular basis distinguishing the disease-associated protein (?SD) from its normal counterpart remains poorly understood. However, recent research suggests that a prion-like mechanism could be involved in the inter-cellular and inter-molecular propagation of aggregation of the protein within the nervous system.ResultsOur data confirm our previous observations of disease acceleration in a transgenic mouse line (M83) overexpressing a mutated (A53T) form of human ?S, following inoculation of either brain extracts from sick M83 mice or fibrillar recombinant ?S. A similar phenomenon is observed following a "second passage" in the M83 mouse model, including after stereotactic inoculations into the hippocampus or cerebellum. For further molecular analyses of ?SD, we designed an ELISA test that identifies ?SD specifically in sick mice and in the brain regions targeted by the pathological process in this mouse model. ?SD distribution, mainly in the caudal brain regions and spinal cord, overall appears remarkably uniform, whatever the conditions of experimental challenge. In addition to specific detection of ?SD immunoreactivity using an antibody against Ser129 phosphorylated ?S, similar results were observed in ELISA with several other antibodies against the C-terminal part of ?S, including an antibody against non phosphorylated ?S. This also indicated consistent immunoreactivity of the murine ?S protein specifically in the affected brain regions of sick mice.ConclusionsPrion-like behaviour in propagation of the disease-associated ?S was confirmed with the M83 transgenic mouse model, that could be followed by an ELISA test. The ELISA data question their possible relationship with the conformational differences between the disease-associated ?S and its normal counterpart.

Project description:Parkinson's disease and related disorders are neuropathologically characterized by cellular deposits of misfolded and aggregated ?-synuclein in the CNS. Disease-associated ?-synuclein adopts a conformation that causes it to form oligomers and fibrils, which have reduced solubility, become hyperphosphorylated, and contribute to the spatiotemporal spreading of pathology in the CNS. The infectious properties of disease-associated ?-synuclein, e.g., by which peripheral route and with which efficiency it can be transmitted, are not fully understood. Here, we investigated the potential of ?-synuclein fibrils to induce neurological disease in TgM83+/- mice expressing the A53T mutant of human ?-synuclein after oral or intravenous challenge and compared it to intraperitoneal and intracerebral challenge. Oral challenge with 50 µg of ?-synuclein fibrils caused neurological disease in two out of eight mice in 220 days and 350 days, and challenge with 500 µg in four out of eight mice in 384?±?131 days, respectively. Intravenous challenge with 50 µg of ?-synuclein fibrils led to disease in 208?±?20 days in 10 out of 10 mice and was in duration comparable to intraperitoneal challenge with 50 µg of ?-synuclein fibrils, which caused disease in 10 out of 10 mice in 202?±?35 days. Ten out of 10 mice that were each intracerebrally challenged with 10 µg or 50 µg of ?-synuclein fibrils developed disease in 156?±?20 days and 133?±?4 days, respectively. The CNS of diseased mice displayed aggregates of sarkosyl-insoluble and phosphorylated ?-synuclein, which colocalized with ubiquitin and p62 and were accompanied by gliosis indicative of neuroinflammation. In contrast, none of the control mice that were challenged with bovine serum albumin via the same routes developed any neurological disease or neuropathology. These findings are important, because they show that ?-synuclein fibrils can neuroinvade the CNS after a single oral or intravenous challenge and cause neuropathology and disease.

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Pathological ?-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.

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Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.

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