Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease

Abstract

Alpha-synuclein is a presynaptic protein expressed throughout the central nervous system, and it is the main component of Lewy bodies, one of the histopathological features of Parkinson's disease (PD) which is a progressive and irreversible neurodegenerative disorder. The conformational flexibility of α-synuclein allows it to adopt different conformations, i.e., bound to membranes or form aggregates, the oligomers are believed to be the more toxic species. In this review, we will focus on two major features of α-synuclein, transmission and toxicity, that could help to understand the pathological characteristics of PD. One important feature of α-synuclein is its ability to be transmitted from neuron to neuron using mechanisms such as endocytosis, plasma membrane penetration or through exosomes, thus propagating the Lewy body pathology to different brain regions thereby contributing to the progressiveness of PD. The second feature of α-synuclein is that it confers cytotoxicity to recipient cells, principally when it is in an oligomeric state. This form causes mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, proteasome impairment, disruption of plasma membrane and pore formation that lead to apoptosis pathway activation and consequent cell death. The complexity of α-synuclein oligomerization and formation of toxic species could be a major factor for the irreversibility of PD and could also explain the lack of successful therapies to halt the disease.

Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72 -ALS/FTD

“…A growing body of evidence has uncovered a propensity for disease relevant proteins such as poly-glutamine, α-synuclein, β-amyloid, SOD1, and TDP43, to be transmitted from cell-to-cell and to seed template nucleation (Feiler et al, 2015; Gallegos et al, 2015; Kanouchi et al, 2012; Nath et al, 2012; Ren et al, 2009; Silverman et al, 2016). Mechanisms of transmission involve secretion of exosomes (Bellingham et al, 2012; Danzer et al, 2012; Pant et al, 2012; Saman et al, 2012), tunneling nanotubes, hemi-channels between cells, exocytosis and endocytosis of proteins, and phagocytosis of infected cells or cellular debris (Costanzo and Zurzolo, 2013; Gallegos et al, 2015). These protein spreading modalities are now commonly interpreted as a mechanism underlying the progressive nature of many neurodegenerative diseases.…”

Understanding Caffeine’s Role in Attenuating the Toxicity of α-Synuclein Aggregates: Implications for Risk of Parkinson’s Disease

“…Our results provide a rationale for the observed epidemiological link between coffee drinking and PD. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Keywords Amorphous aggregates; Caffeine; Fibrillation; Quenching; α-Synuclein 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 [2][3][4] These approaches provide temporary symptomatic relief but do not modify the course of the disease. As the presence of cytosolic inclusions seems to have adverse effects on cell survival, efforts are on to develop strategies which can slow down or inhibit aggregation of α-synuclein.…”

“…Its aggregation is likely to result in reduced cell viability due to "loss of function", apart from a probable "gain of function" mechanism of the proteotoxic aggregates themselves. 1,2 PD is increasingly classified as an environmental disorder. 9,10 As such, lifestyle habits like consumption of tea, coffee, alcohol and cigarette smoking have shown correlation with the occurrence of the disease.…”

How close are we to revealing the etiology of Parkinson's disease?

“…It is a multiorgan disease characterized by progressive degeneration of the dopaminergic nigrostriatal system, many other neuronal systems and organs responsible for the core motor symptoms -rigidity, akinesia, rest tremor and postural instabilityand a variety of non-motor and neuropsychological manifestations that affect the patient's quality of life. Much attention has been focused on abnormal aSyn, which represents the major component of many intracellular and intraneuritic deposits (Lewy bodies and dystrophic neurites, the morphological hallmark of PD [1,2]), while mutations in the aSyn locus and related genes can cause lessfrequent inherited forms of PD [3,4]. Other etiologies underlying parkinsonisms, like tauopathies or other neurodegenerative disorders, are not considered here.…”

“…Disturbed calcium homeostasis, abnormal cortical metabolism and other molecular changes due to the convergence of multiple deficits have been observed in early stages of PD [16]. Overwhelming evidence has emerged showing that deposition of misfolded aSyn and its oligomers in the cytoplasm of selected neuronal populations, as well as their interaction with other proteins, particularly in their oligomeric forms, which might synergistically promote their mutual aggregation and vice versa, play a critical role in amplifying neuronal damage [1,2,13,15]. However, the basic mechanisms leading to the intimate association and synergism of these proteins, suggesting a dualism or triad of amyloidogenic neurodegeneratiom await further clarification.…”