Evidence for cross-hemispheric preconditioning in experimental Parkinson’s disease

Abstract

Dopamine loss and motor deficits in Parkinson's disease typically commence unilaterally and remain asymmetric for many years, raising the possibility that endogenous defenses slow the cross-hemispheric transmission of pathology. It is well-established that the biological response to subtoxic stress prepares cells to survive subsequent toxic challenges, a phenomenon known as preconditioning, tolerance, or stress adaptation. Here we demonstrate that unilateral striatal infusions of the oxidative toxicant 6-hydroxydopamine (6-OHDA) precondition the contralateral nigrostriatal pathway against the toxicity of a second 6-OHDA infusion in the opposite hemisphere. 6-OHDA-induced loss of dopaminergic terminals in the contralateral striatum was ablated by cross-hemispheric preconditioning, as shown by two independent markers of the dopaminergic phenotype, each measured by two blinded observers. Similarly, loss of dopaminergic somata in the contralateral substantia nigra was also abolished, according to two blinded measurements. Motor asymmetries in floor landings, forelimb contacts with a wall, and spontaneous turning behavior were consistent with these histological observations. Unilateral 6-OHDA infusions increased phosphorylation of the kinase ERK2 and expression of the antioxidant enzyme CuZn superoxide dismutase in both striata, consistent with our previous mechanistic work showing that these two proteins mediate preconditioning in dopaminergic cells. These findings support the existence of cross-hemispheric preconditioning in Parkinson's disease and suggest that dopaminergic neurons mount impressive natural defenses, despite their reputation as being vulnerable to oxidative injury. If these results generalize to humans, Parkinson's pathology may progress slowly and asymmetrically because exposure to a disease-precipitating insult induces bilateral upregulation of endogenous defenses and elicits cross-hemispheric preconditioning.

Pronounced α-Synuclein Pathology in a Seeding-Based Mouse Model Is Not Sufficient to Induce Mitochondrial Respiration Deficits in the Striatum and Amygdala

“…To investigate potential qualitative changes in respiration patterns, we calculated FCRs ( Gnaiger, 2009 ) and detected a reduced succinate-driven FCR in corticosterone conditions in the striatum. A higher succinate-driven FCR after the surgical intervention in the absence of exogenous corticosterone might be an adaptative response of the damaged tissue ( Lukyanova and Kirova, 2015 ; Weilnau et al, 2018 ). Protein aggregation is believed to induce conditioning-like cellular adaptations ( Mao and Crowder, 2010 ).…”

Enhancing and Extending Biological Performance and Resilience

“…Indeed, the correlation between disease duration and disease severity/dose may underlie the U-shaped profile of the early compensatory changes in neurodegenerative disorders when plotted as a function of time from disease onset. 32 Another example of the critical importance of the temporal dimension is that the duration of the recovery interval between two stressors also determines the direction of stress response (see discussion in 43 ). In other words, stimuli applied without a sufficient recovery interval might potentiate lethality or toxicity instead of conditioning the organism.…”

“… 210 Somewhat analogously, unilateral dopaminergic neurotoxicity elicits “cross-hemispheric” conditioning and completely prevents behavioral deficits and cell loss in response to a second hit in the opposite hemisphere, which may explain the asymmetrical nature of dopaminergic cell loss and motor deficits in early Parkinson disease. 43 Aside from nitrite, adenosine, or inflammatory factors such as potential diffusible mediators of remote preconditioning, 204 , 211 , 212 extracellular vesicles such as exosomes, microvesicles, and apoptotic bodies containing peptides, proteins, microRNA (eg, miR-144), and DNA may also convey long-distance communication in remote conditioning. 213 – 215 Perhaps because remote conditioning is dependent on freely diffusible factors, its benefits are independent of the ischemic region.…”

Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

“…To investigate potential qualitative changes in respirational patterns, we calculated FCRs (Gnaiger, 2009), and detected a reduced succinate-driven FCR in corticosterone conditions in the striatum. Higher succinate-driven FCR after the surgical intervention in the absence of exogenous corticosterone might be an adaptation response of the damaged tissue (Lukyanova and Kirova, 2015; Weilnau et al, 2018). Protein aggregation is believed to induce conditioning-like cellular adaptations (Mao and Crowder, 2010).…”