Initiation and propagation of α-synuclein aggregation in the nervous system

Abstract

The two main pathological hallmarks of Parkinson's disease are loss of dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly of α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one of the most effective treatment for alleviating the motor symptoms of Parkinson's disease (Olanow, Mov Disord 34:812-815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) to modulate basal ganglia circuit activity successfully alleviates some motor symptoms. MRI guided focused ultrasound in the subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez et al., Lancet Neurol 17:54-63, 2018). However, to date, there exists no treatment that stops the progression of this disease. The findings that α-synuclein can be released from neurons and inherited through interconnected neural networks opened the door for discovering novel treatment strategies to prevent the formation and spread of Lewy pathology with the goal of halting PD in its tracks. This hypothesis is based on discoveries that pathologic aggregates of α-synuclein induce the endogenous α-synuclein protein to adopt a similar pathologic conformation, and is thus self-propagating. Phase I clinical trials are currently ongoing to test treatments such as immunotherapy to prevent the neuron to neuron spread of extracellular aggregates. Although tremendous progress has been made in understanding how Lewy pathology forms and spreads throughout the brain, cell intrinsic factors also play a critical role in the formation of pathologic α-synuclein, such as mechanisms that increase endogenous α-synuclein levels, selective expression profiles in distinct neuron subtypes, mutations and altered function of proteins involved in α-synuclein synthesis and degradation, and oxidative stress. Strategies that prevent the formation of pathologic α-synuclein should consider extracellular release and propagation, as well as neuron intrinsic mechanisms.

Detecting Oxidative Stress Biomarkers in Neurodegenerative Disease Models and Patients

“…Lewy bodies contain aggregated α-synuclein as a main component, as well as a number of other proteins and lipid membrane fragments. Aggregation of misfolded α-synuclein can impair axonal transport and proteostasis, leading to degeneration of neurites and cell death [22,23].…”

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

“…Normally, α-synuclein is encoded by multiple genes on the autosome and is responsible for regulating dopamine metabolism. When this gene is mutated, it can cause the pathological accumulation of α-synuclein to form Lewy bodies and stimulate neuronal degeneration [ 124 , 125 , 126 , 127 ]. In addition to genetic mutations of α-synuclein gene, increased post-translational modifications of this protein under elevated oxidative stress in PD could result in the accumulation and/or aggregation of its oligomers [ 120 ].…”

“…It was shown that α-synuclein is degraded by chaperone-mediated autophagy (CMA) and macroautophagy pathways, where CMA is the main mechanism [ 129 , 130 ]. However, mutated α-synuclein leads to its decreased binding to chaperone protein molecules in CMA, leading to the formation of Lewy bodies [ 124 , 126 ]. Some cases of familial PD were related to the repeated expression of the α-synuclein gene.…”

Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases

“…In addition to AD, MT dysfunction has been considered an important contributor also to the pathogenesis of Parkinson’s disease (PD), a neurodegenerative condition characterized by the loss of dopaminergic neurons from substantia nigra and the presence in these cells of intracellular inclusions of α-synuclein (α-syn) [ 266 ].…”