Nigral proteasome inhibition in mice leads to motor and non-motor deficits and increased expression of Ser129 phosphorylated α-synuclein

Abstract

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.

Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

“…The elevated body swing test used here to evaluate motor performance was highly predictive of the degree of nigrostriatal injury as previously reported (3,8). It provided the first evidence of a beneficial effect of DMF that was further confirmed by preservation at 1, 3, and 8 weeks from surgery of TH + neuron bodies in the SN and fibers in the STR in Nrf2 +/+ but not Nrf2 -/-mice.…”

“…The elevated body swing test is a simple and easy behavioral test that only requires handling the animal by its tail and recording the direction of swings made by the animal for a certain period (3,8). Briefly, the animal was held in the vertical axis and a swing was recorded whenever the animal moved its head out of the vertical axis to either side.…”

Neuroprotective Potential of Polydatin Against Motor Abnormalities and Dopaminergic Neuronal Loss in Rotenone Induced Parkinson Model

“…This could be due to global impairment in coordinated and skilled movements of forelimb, less motivation or decrease tactile stimuli (Bentea et al, 2015). Decreased time to adhesive removal by polydatin+rotenone treated animals, could be due to neuro protection by boosting, tactile perception, coordination of movements and motivation secondary to amelioration in function of premotor cortex and cerebellum.…”

MicroRNA expressing profiles in A53T mutant alpha-synuclein transgenic mice and Parkinsonian

“…Once mouse randomly was placed in the box, the travel distance was recorded in the field (4 cm from the middle line) [80]. Male mice were tested 3 times individually for wild-type and A53T transgenic mice ( n = 6).…”