Role of neurotoxicants and traumatic brain injury in α-synuclein protein misfolding and aggregation

Abstract

Protein misfolding and aggregation are key pathological features of many neurodegenerative diseases including Parkinson’s disease (PD) and other forms of human Parkinsonism. PD is a complex and multifaceted disorder whose etiology is not fully understood. However, several lines of evidence support the multiple hit hypothesis that genetic vulnerability and environmental toxicants converge to trigger PD pathology. Alpha-synuclein (α-Syn) aggregation in the brain is an important pathophysiological characteristic of synucleinopathies including PD. Epidemiological and experimental studies have shown that metals and pesticides play a crucial role in α-Syn aggregation leading to the onset of various neurodegenerative diseases including PD. In this review, we will emphasize key findings of several epidemiological as well as experimental studies of metal- and pesticide-induced α-Syn aggregation and neurodegeneration. We will also discuss other factors such as traumatic brain injury and oxidative insult in the context of α-Syn-related neurodegenerative processes.

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

“…Parkinson’s disease-related neurodegeneration is likely to occur several decades before the onset of the motor symptoms [20]. Associated with different potentially pathogenic risk factors (toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, genomic defects), PD neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta and Lewy body deposition, with widespread involvement of other CNS structures and peripheral tissues [21,22,23]. Parkinson’s disease is a form of multisystemic α-synucleinopathy with Lewy bodies deposited in the midbrain.…”

“…Parkinson’s disease is a form of multisystemic α-synucleinopathy with Lewy bodies deposited in the midbrain. Descriptive phenomena to explain in part this neuropathological phenotype include the following: (i) genomic factors; (ii) epigenetic changes; (iii) toxic factors; (iv) oxidative stress anomalies; (v) neuroimmune/neuroinflammatory reactions; (vi) hypoxic-ischemic conditions; (vii) metabolic deficiencies; and (viii) ubiquitin–proteasome system dysfunction [19,23,24,25,26,27,28,29]; all these conditions leading to protein misfolding and aggregation and premature neuronal death. Recent evidence also suggests that PD might be a prion-like disease [30].…”

Acrolein-mediated alpha-synuclein pathology involvement in the early post-injury pathogenesis of mild blast-induced Parkinsonian neurodegeneration

“…It is a small, soluble protein that is highly localized in presynaptic terminals (Khan et al, 2012;Maroteaux et al, 1988), and can be essential to normal brain function (Galvin et al, 2001;Kim et al, 2000;Souza et al, 2000;Takeda et al, 1998). While its exact function(s) are not completely understood, α-syn has been reported to facilitate membrane trafficking, dopamine regulation, and synaptic plasticity (Rokad et al, 2016). Overexpression of α-syn has been observed in animal models of TBI (Acosta et al, 2015;Shahaduzzaman et al, 2013;Surgucheva et al, 2014;Uryu et al, 2003), but the mechanisms by which PD-like neuropathologies are exacerbated by TBI remain ambiguous.…”

Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders?

“…Candidate genes which have been reported to be associated with PD include e.g., β-glucocerebrosidase ( GBA ), diacylglycerol kinase θ, 110kD ( GAK-DGKQ ), SNCA , human leukocyte antigen ( HLA ), RAD51B, DYRK1A, CHCHD2, VPS35, RAB39B or TMEM230 [ 84 , 85 ]. Different mechanisms, including genomic factors, epigenetic changes, toxic factors, mitochondrial dysfunction, oxidative stress, neuroimmune/neuroinflammatory reactions, hypoxic-ischemic conditions, metabolic deficiencies and ubiquitin–proteasome system dysfunction, seem to be involved in PD pathogenesis [ 84 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ]. Mitochondrial dysfunction has been shown to be linked to mutations in PINK1 and DJ1 genes [ 87 , 88 ].…”