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Autonomic ganglionic injection of ?-synuclein fibrils as a model of pure autonomic failure ?-synucleinopathy.

ABSTRACT: ?-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), ?-synuclein (?-Syn) pathology is confined within the autonomic nervous system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking. Here, we show that in TgM83+/- mice, inoculation of ?-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of ?-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally. In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction. Thus, we have generated a mouse model of pure autonomic dysfunction caused by ?-Syn pathology. This model may help define the mechanistic link between transmission of pathological ?-Syn and the cardinal features of autonomic dysfunction in ?-synucleinopathy.

SUBMITTER: Wang XJ

PROVIDER: S-EPMC7028908 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Autonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy.

Wang Xue-Jing XJ Ma Ming-Ming MM Zhou Le-Bo LB Jiang Xiao-Yi XY Hao Miao-Miao MM Teng Robert K F RKF Wu Erxi E Tang Bei-Sha BS Li Jia-Yi JY Teng Jun-Fang JF Ding Xue-Bing XB

Nature communications 20200218 1

α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), α-synuclein (α-Syn) pathology is confined within the autonomic nervous system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking. Here, we show that in TgM83<sup>+/-</sup> mice, inoculation of α-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of α-Syn pathology only through the autonomic pathw ...[more]

PMID: 32071315

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Project description:BACKGROUND:Imbalanced activation of the cardiac autonomic nervous system triggers postoperative atrial fibrillation (POAF). Neuronal calcium overload induces apoptosis. We hypothesize that epicardial injection of timed-release nanoformulated CaCl2 (nCaCl2) into left atrial ganglionic plexi (GP) modulates autonomic function and suppresses POAF. OBJECTIVE:The purpose of this study was to determine whether nCaCl2 GP therapy suppresses POAF. METHODS:We used a novel canine model of POAF with implanted radiotelemetry to record nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus nerve, and GP. At week 3, nCaCl2 (n = 7) or vehicle control (sham; n = 3) was injected into left pulmonary vein GP (LGP), followed by right pulmonary vein GP at week 4. Atrial effective refractory period (AERP) and atrial fibrillation vulnerability (AFV) were assessed in vivo. Resting and exercise NA and heart rate (HR) were assessed before and after LGP treatment. RESULTS:AERP decreased (P < .0001) and AFV increased (P = .008) at week 3 vs baseline. However, nCaCl2-LGP treatment reversed these changes and restored them to baseline after 1 week (P = .04). Subsequent nCaCl2-right pulmonary vein GP treatment further reduced AFV (P = .03). In contrast, AFV increased (P = .001) and AERP remained decreased (P = .01) 1 week after sham-LGP treatment vs baseline. nCaCl2-LGP treatment reduced NA from GP (P < .02) and NA from the left cardiac vagus nerve (P < .05) and increased SNA (P < .02). Despite increased SNA, HR was decreased (P < .01) with loss of HR-SNA correlation (R = 0.62). After sham-LGP treatment, NA was unchanged and HR-SNA remained correlated (R = 0.95). Histology confirmed nCaCl2-GP colocalization, apoptosis, and loss of immunoreactivity in nCaCl2-treated somas. CONCLUSION:Epicardial injection of nCaCl2 into left atrial GP induced neuroapoptosis and modulated autonomic function. This reversed a postoperative reduction in AERP and suppressed POAF.

Project description:Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-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 α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-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). α-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 α-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 α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

Dataset Information

Autonomic ganglionic injection of ?-synuclein fibrils as a model of pure autonomic failure ?-synucleinopathy.

Publications

Autonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy.

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