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L444P Gba1 mutation increases formation and spread of ?-synuclein deposits in mice injected with mouse ?-synuclein pre-formed fibrils.

ABSTRACT: Parkinson disease is the most common neurodegenerative movement disorder, estimated to affect one in twenty-five individuals over the age of 80. Mutations in glucocerebrosidase 1 (GBA1) represent the most common genetic risk factor for Parkinson disease. The link between GBA1 mutations and ?-synuclein accumulation, a hallmark of Parkinson disease, is not fully understood. Following our recent finding that Gba1 mutations lead to increased ?-synuclein accumulation in mice, we have studied the effects of a single injection of mouse ?-synuclein pre-formed fibrils into the striatum of Gba1 mice that carry a L444P knock-in mutation. We found significantly greater formation and spread of ?-synuclein inclusions in Gba1-transgenic mice compared to wild-type controls. This indicates that the Gba1 L444P mutation accelerates ?-synuclein pathology and spread.

SUBMITTER: Migdalska-Richards A

PROVIDER: S-EPMC7444808 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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L444P Gba1 mutation increases formation and spread of α-synuclein deposits in mice injected with mouse α-synuclein pre-formed fibrils.

Migdalska-Richards Anna A Wegrzynowicz Michal M Harrison Ian F IF Verona Guglielmo G Bellotti Vittorio V Spillantini Maria Grazia MG Schapira Anthony H V AHV

PloS one 20200824 8

Parkinson disease is the most common neurodegenerative movement disorder, estimated to affect one in twenty-five individuals over the age of 80. Mutations in glucocerebrosidase 1 (GBA1) represent the most common genetic risk factor for Parkinson disease. The link between GBA1 mutations and α-synuclein accumulation, a hallmark of Parkinson disease, is not fully understood. Following our recent finding that Gba1 mutations lead to increased α-synuclein accumulation in mice, we have studied the effe ...[more]

PMID: 32833982

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Project description:Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (?-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated ?-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse ?-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant ?-syn or PFF mouse ?-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant ?-syn and PFF ?-syn injections resulted in phosphorylated ?-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). ?-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although ?-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that ?-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous ?-syn to induce a progressive, neurodegenerative model of ?-synucleinopathy in rats.

Dataset Information

L444P Gba1 mutation increases formation and spread of ?-synuclein deposits in mice injected with mouse ?-synuclein pre-formed fibrils.

Publications

L444P Gba1 mutation increases formation and spread of α-synuclein deposits in mice injected with mouse α-synuclein pre-formed fibrils.

Similar Datasets

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