Alpha-synuclein aggregation, Ubiquitin proteasome system impairment, and l-Dopa response in zinc-induced Parkinsonism: resemblance to sporadic Parkinson’s disease

Abstract

Alpha-synuclein (α-synuclein) aggregation and impairment of the Ubiquitin proteasome system (UPS) are implicated in Parkinson's disease (PD) pathogenesis. While zinc (Zn) induces dopaminergic neurodegeneration resulting in PD phenotype, its effect on protein aggregation and UPS has not yet been deciphered. The current study investigated the role of α-synuclein aggregation and UPS in Zn-induced Parkinsonism. Additionally, levodopa (L-Dopa) response was assessed in Zn-induced Parkinsonian model to establish its closeness with idiopathic PD. Male Wistar rats were treated with zinc sulfate (Zn; 20 mg/kg; i.p.) twice weekly for 12 weeks along with respective controls. In few subsets, animals were subsequently treated with L-Dopa for 21 consecutive days following Zn exposure. A significant increase in total and free Zn content was observed in the substantia nigra of the brain of exposed groups. Zn treatment caused neurobehavioral anomalies, striatal dopamine decline, and dopaminergic neuronal cell loss accompanied with a marked increase in α-synuclein expression/aggregation and Ubiquitin-conjugated protein levels in the exposed groups. Zn exposure substantially reduced UPS-associated trypsin-like, chymotrypsin-like, and caspase-like activities along with the expression of SUG1 and β-5 subunits of UPS in the nigrostriatal tissues of exposed groups. L-Dopa treatment rescued from Zn-induced neurobehavioral deficits and restored dopamine levels towards normalcy; however, Zn-induced dopaminergic neuronal loss, reduction in tyrosine hydroxylase expression, and increase in oxidative stress were unaffected. The results suggest that Zn caused UPS impairment, resulting in α-synuclein aggregation subsequently leading to dopaminergic neurodegeneration, and that Zn-induced Parkinsonism exhibited positive L-Dopa response similar to sporadic PD.

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

“…Addition of increasing Zn 2+ may interact with specific regions of ubiquitin and promote proteinprotein contacts [109]. And zinc caused UPS impairment resulting in α-synuclein aggregation subsequently leading to dopaminergic neurodegeneration [110]. In PC12 cell, zinc-induced autophagosome formation facilitates cell survival [111].…”

Cross-talk between redox signalling and protein aggregation

“…Ubiquitinated proteins and insoluble aggregates are pulled through the proteasomal ring-like structure, to be broken down by proteolysis. Not surprisingly, proteasomal dysfunction is associated with ageing and leads to the accumulation of aggregates [5][6][7]9,10], catalyzing a chain reaction in which aggregates block the proteasome which causes further dysfunction [37].…”

“…This might be partly due to the fact that ROS, in the form of H 2 O 2 , itself plays a dual role. While at lower levels H 2 O 2 acts as a second messenger in redox signalling, which is absolutely required for physiology and for lifespan extension in model systems [2], at higher levels H 2 O 2 and other ROS could lead to random damage including for instance protein unfolding and aggregation, and the latter has been proposed to accelerate the aging process [3][4][5][6][7][8][9][10]. But there is also evidence of functional redox signalling-dependent protein aggregation, for instance providing a means to (temporarily) inactivate or alter the function of proteins.…”

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

“…This zinc-induced Parkinsonism showed a loss of dopaminergic cells, motor impairment, aggregation of α-syn and impairment of UPS-mediated degradation. Altogether, zinc exposure induced consequences that were similar to those seen in sporadic PD and were reversible by treatment with L-DOPA [454].…”