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Chronic nigral neuromodulation aggravates behavioral deficits and synaptic changes in an ?-synuclein based rat model for Parkinson's disease.

ABSTRACT: Aggregation of alpha-synuclein (?-SYN) is the pathological hallmark of several diseases named synucleinopathies, including Parkinson's disease (PD), which is the most common neurodegenerative motor disorder. Alpha-SYN has been linked to synaptic function both in physiological and pathological conditions. However, the exact link between neuronal activity, ?-SYN toxicity and disease progression in PD is not clear. In this study, we aimed to investigate the effect of chronic neuromodulation in an ?-SYN-based rat model for PD using chemogenetics. To do this, we expressed excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) combined with mutant A53T ?-SYN, using two different recombinant adeno-associated viral (rAAV) vectors (serotypes 2/7 and 2/8) in rat substantia nigra (SN) and investigated the effect on motor behavior, synapses and neuropathology. We found that chronic neuromodulation aggravates motor deficits induced by ?-SYN, without altering dopaminergic neurodegeneration. In addition, neuronal activation led to changes in post-translational modification and subcellular localization of ?-SYN, linking neuronal activity to the pathophysiological role of ?-SYN in PD.

SUBMITTER: Torre-Muruzabal T

PROVIDER: S-EPMC6805517 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Chronic nigral neuromodulation aggravates behavioral deficits and synaptic changes in an α-synuclein based rat model for Parkinson's disease.

Torre-Muruzabal Teresa T Devoght Jens J Van den Haute Chris C Brône Bert B Van der Perren Anke A Baekelandt Veerle V

Acta neuropathologica communications 20191022 1

Aggregation of alpha-synuclein (α-SYN) is the pathological hallmark of several diseases named synucleinopathies, including Parkinson's disease (PD), which is the most common neurodegenerative motor disorder. Alpha-SYN has been linked to synaptic function both in physiological and pathological conditions. However, the exact link between neuronal activity, α-SYN toxicity and disease progression in PD is not clear. In this study, we aimed to investigate the effect of chronic neuromodulation in an α ...[more]

PMID: 31640762

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Project description:Parkinson's disease is a neurodegenerative disorder characterized by motor and non-motor disturbances. Various pathogenic pathways drive disease progression including oxidative stress, mitochondrial dysfunction, α-synuclein aggregation and impairment of protein degradation systems. Dysfunction of the ubiquitin-proteasome system in the substantia nigra of Parkinson's disease patients is believed to be one of the causes of protein aggregation and cell death associated with this disorder. Lactacystin, a potent inhibitor of the proteasome, was previously delivered to the nigrostriatal pathway of rodents to model nigrostriatal degeneration. Although lactacystin-treated animals develop parkinsonian motor impairment, it is currently unknown whether they also develop non-motor symptoms characteristic of this disorder. In order to further describe the proteasome inhibition model of Parkinson's disease, we characterized the unilateral lactacystin model, performed by stereotaxic injection of the toxin in the substantia nigra of mice. We studied the degree of neurodegeneration and the behavioral phenotype 1 and 3 weeks after lactacystin lesion both in terms of motor impairment, as well as non-motor symptoms. We report that unilateral administration of 3 μg lactacystin to the substantia nigra of mice leads to partial (~40%) dopaminergic cell loss and concurrent striatal dopamine depletion, accompanied by increased expression of Ser129-phosphorylated α-synuclein. Behavioral characterization of the model revealed parkinsonian motor impairment, as well as signs of non-motor disturbances resembling early stage Parkinson's disease including sensitive and somatosensory deficits, anxiety-like behavior, and perseverative behavior. The consistent finding of good face validity, together with relevant construct validity, warrant a further evaluation of proteasome inhibition models of Parkinson's disease in pre-clinical research and validation of therapeutic targets.

Dataset Information

Chronic nigral neuromodulation aggravates behavioral deficits and synaptic changes in an ?-synuclein based rat model for Parkinson's disease.

Publications

Chronic nigral neuromodulation aggravates behavioral deficits and synaptic changes in an α-synuclein based rat model for Parkinson's disease.

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