Evolution of Extra-Nigral Damage Predicts Behavioural Deficits in a Rat Proteasome Inhibitor Model of Parkinson's Disease

Abstract

Establishing the neurological basis of behavioural dysfunction is key to provide a better understanding of Parkinson's disease (PD) and facilitate development of effective novel therapies. For this, the relationships between longitudinal structural brain changes associated with motor behaviour were determined in a rat model of PD and validated by post-mortem immunohistochemistry. Rats bearing a nigrostriatal lesion induced by infusion of the proteasome inhibitor lactacystin into the left-medial forebrain bundle and saline-injected controls underwent magnetic resonance imaging (MRI) at baseline (prior to surgery) and 1, 3 and 5 weeks post-surgery with concomitant motor assessments consisting of forelimb grip strength, accelerating rotarod, and apormorphine-induced rotation. Lactacystin-injected rats developed early motor deficits alongside decreased ipsilateral cortical volumes, specifically thinning of the primary motor (M1) and somatosensory cortices and lateral ventricle hypertrophy (as determined by manual segmentation and deformation-based morphometry). Although sustained, motor dysfunction and nigrostriatal damage were maximal by 1 week post-surgery. Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5. Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor. These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

Proteostasis and Movement Disorders: Parkinson's Disease and Amyotrophic Lateral Sclerosis

“…It is thought that neurodegeneration arises from the formation of toxic misfolded oligomers of a-synuclein that may exert their toxic effects by disrupting cell membranes such as those of the mitochondria. a-Synuclein proteostasis depends on both the ubiquitin-proteasome and lysosomal pathways of protein turnover, so disruption of either of these pathways by, e.g., proteasome inhibitors and lysosomal storage diseases, might be expected to lead to increased accumulation of a-synuclein and eventually to the formation of a-synuclein aggregates (Lopez and Sidransky 2010;Vernon et al 2011). The role of the large Lewy body aggregates is controversial.…”

Decreased behavioral response to intranigrally administered GABAA agonist muscimol in the lactacystin model of Parkinson's disease may result from partial lesion of nigral non-dopamine neurons: Comparison to the classical neurotoxin 6-OHDA

“…While some in vitro studies demonstrated particular sensitivity of DA neurons to the action of these compounds [11,26,27], other reports showed only slight differences between vulnerability of DA and ␥-aminobutyric acid (GABA) neurons [12], or even a greater resistance of DA neurons compared to non-DA ones [28]. In turn, there is a clear evidence from magnetic resonance imaging studies that the administration of lactacystin into the rat SN pars compacta (SNc) or medial forebrain bundle (MFB) results in widespread extra-nigral volume changes [18,19,24]. Qualitative assessment confirmed that lactacystin, besides the death of DA neurons in the SNc, produced additional neuronal loss in the SN pars reticulata (SNr), ventral tegmental area (VTA), thalamus and certain extranigral nuclei in proximity to the injection tract [18,19].…”

“…Neuronal degeneration was accompanied by a sharp decrease in the striatal DA content and impairment of the motor dysfunction, reversed by l-DOPA treatment [21]. Furthermore, lactacystin treatment led to the formation of cytoplasmic ␣-synuclein-and ubiquitinimmunopositive inclusion in the SN [18,19,[22][23][24][25]. Thus, the advantage of the lactacystin model over the conventional 6-OHDA model is that, besides the loss of DA neurons in the SN, it represents the cardinal feature of PD, namely abnormal protein degradation.…”

“…A number of studies have shown that lactacystin induces death of DA cells in vitro [10][11][12][13] as well as degeneration of nigral DA neurons in vivo [14][15][16][17][18][19][20]. Neuronal degeneration was accompanied by a sharp decrease in the striatal DA content and impairment of the motor dysfunction, reversed by l-DOPA treatment [21].…”

“…In turn, there is a clear evidence from magnetic resonance imaging studies that the administration of lactacystin into the rat SN pars compacta (SNc) or medial forebrain bundle (MFB) results in widespread extra-nigral volume changes [18,19,24]. Qualitative assessment confirmed that lactacystin, besides the death of DA neurons in the SNc, produced additional neuronal loss in the SN pars reticulata (SNr), ventral tegmental area (VTA), thalamus and certain extranigral nuclei in proximity to the injection tract [18,19]. Furthermore, intranigral administration of lactacystin induced a moderate decrease in acetylcholine (ACh) neurons in the pedunculopontine nucleus (PPN) as revealed by the stereological analysis [24] which replicates cholinergic deficits observed in PD [29].…”