English
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Currently, PD is incurable, and the diagnosis of PD mainly relies on clinical manifestations. The central pathological event in PD is the abnormal aggregation and deposition of misfolded α-synuclein (α-Syn) protein aggregates in the Lewy body (LB) in affected brain areas. Behaving as a prion-like seeding, the misfolded α-syn protein can induce and facilitate the aggregation of native unfolded α-Syn protein to aggravate α-Syn protein aggregation, leading to PD progression. Recently, in a blood-based α-Syn seeding amplification assay (SAA), Kluge et al. identified pathological α-Syn seeding activity in PD patients with Parkin (PRKN) gene variants. Additionally, pathological α-syn seeding activity was also identified in sporadic PD and PD patients with Leucine-rich repeat kinase 2 (LRRK2) or glucocerebrosidase (GBA) gene variants. Principally, the α-Syn SAA can be used to detect pathological α-Syn seeding activity, which will significantly enhance PD diagnosis, progression monitoring, prognosis prediction, and anti-PD therapy. The significance and future strategies of α-Syn SAA protocol are highlighted and proposed, whereas challenges and limitations of the assay are discussed.
Keywords:
α-synuclein; biomarker; neurodegeneration; Parkinson’s disease; seeding amplification assay
1. Introduction
Parkinson’s Disease (PD) is the second most common neurodegenerative disorder that is clinically diagnosed based on motor symptoms (bradykinesia, tremor, rigidity, hypomimia, shuffling gait, difficulty walking, and postural instability) and non-motor symptoms (cognitive decline, autonomous disorders, disrupted sleep, and sensory disturbances) [1,2,3]. The progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and the deposition of cytoplasmic protein inclusions referred to as Lewy bodies (LBs) in affected brain areas are two pathological hallmarks of PD [4]. Motor symptoms usually occur late in the neurodegenerative process in PD patients, as more than half of striatal dopaminergic neurons are lost when motor symptoms occur [3]. Non-motor symptoms may precede the development of motor symptoms, and thus, can be considered a prodromal state of PD [5]. So far, the exact pathogenesis mechanism behind PD is still unknown. It has been suggested that endogenous dopamine (DA) can be considered an endogenous pathogenic factor for PD [6]. In dopaminergic neurons, DA can undergo auto-oxidation and enzyme-catalyzed metabolism to generate deleterious oxidative DA metabolites, including reactive oxygen species (ROS), DA quinones (DAQs), 3,4-dihydroxyphenylacetaldehyde (DOPAL), and neuromelanin (NM), contributing to the dopaminergic neuron impairment [6,7].
Currently, PD is still an incurable neurodegenerative disease without any therapeutic strategy that could halt or reverse the progressive loss of dopaminergic neurons. The levodopa (L-DOPA) replenishing strategy is the current gold standard for clinical PD treatment to alleviate PD symptoms [8]. Numerous active and passive immunotherapies have exhibited promising therapeutic efficacy in preclinical studies, and many of these are currently undergoing clinical trials [9]. Therefore, an objective and reliable biomarker is urgently required to enhance the diagnostic accuracy of PD in its early stage or prodromal state and monitor its progression. Accumulated evidence suggests that the abnormal deposition and spreading of the misfolded and aggregated α-synuclein (α-Syn) proteins are the central molecular events behind PD pathogenesis [10]. The misfolded and aggregated α-Syn protein is involved in multiple cellular dysfunctions, including the disruption of the autophagy-lysosomal pathway, the dysregulation of mitochondrial function, and the disappearance of dopaminergic neurons [10,11]. The toxicity caused by the aggregated α-Syn protein is closely related to DA and DA oxidative metabolites [6,12]. The overexpression of α-Syn enhances the DA-dependent dopaminergic neuron toxicity [13]. DA-derived metabolites, such as DAQs and DOPAL, can conjugate with α-Syn protein to stabilize the deleterious oligomer form α-Syn protein and enhance α-Syn protein toxicity [14,15,16,17]. Moreover, α-Syn protein promotes the synthesis of NM, an insoluble granular pigment, in dopaminergic neurons [18]. NM generates ROS under oxidative stress, and the interaction between NM and α-Syn is identified to induce neuroinflammation and microglia activation related to α-Syn-associated DA neurodegeneration [7,19,20]. Therefore, the misfolded and aggregated form of α-syn protein could be considered a vital pathogenic biomarker in PD.
The article is reprinted from MDPI, original link:https://www.mdpi.com/1422-0067/26/1/389
The FAI climbed 5.9 percent year-on-year in the first 11 months of 2018, quickening from the 5.7-percent growth in Jan-Oct, the National Bureau of Statistics (NBS) said Friday in an online statement.
The key indicator of investment, dubbed a major growth driver, hit the bottom in August and has since started to rebound steadily.
In the face of emerging economic challenges home and abroad, China has stepped up efforts to stabilize investment, in particular rolling out measures to motivate private investors and channel funds into infrastructure.
Friday's data showed private investment, accounting for more than 60 percent of the total FAI, expanded by a brisk 8.7 percent.
NBS spokesperson Mao Shengyong said funds into weak economic links registered rapid increases as investment in environmental protection and agriculture jumped 42 percent and 12.5 percent respectively, much faster than the average.
In breakdown, investment in high-tech and equipment manufacturing remained vigorous with 16.1-percent and 11.6-percent increases respectively in the first 11 months. Infrastructure investment gained 3.7 percent, staying flat. Investment in property development rose 9.7 percent, also unchanged.