Alpha-Synuclein and Mitochondrial Dysfunction in Parkinson's Disease: The Emerging Role of VDAC.
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ABSTRACT:
SUBMITTER: Risiglione P
PROVIDER: S-EPMC8170894 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alpha-synuclein (?S) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). All diseases are determined by ?S aggregate deposition but can be separated into distinct pathological phenotypes and diagnostic criteria. Here we attempt to reinterpret the literature, particularly in terms of how ?S structure may relate to pathology. We do so in the context of a rapidly evolving field, taking into account newly revealed structural information on both native and pathogenic forms of the ?S protein, including recent solid state NMR and cryoEM fibril structures. We discuss how these new findings impact on current understanding of ?S and PD, and where this information may direct the field.
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Project description:Parkinson's disease (PD) is a pathological condition characterized by the aggregation and the resultant presence of intraneuronal inclusions termed Lewy bodies (LBs) and Lewy neurites which are mainly composed of fibrillar α-synuclein (α-syn) protein. Pathogenic aggregation of α-syn is identified as the major cause of LBs deposition. Several mutations in α-syn showing varied aggregation kinetics in comparison to the wild type (WT) α-syn are reported in PD (A30P, E46K, H 50Q, G51D, A53E, and A53T). Also, the cell-to-cell spread of pathological α-syn plays a significant role in PD development. Interestingly, it has also been suggested that the pathology of PD may begin in the gastrointestinal tract and spread via the vagus nerve (VN) to brain proposing the gut-brain axis of α-syn pathology in PD. Despite multiple efforts, the behavior and functions of this protein in normal and pathological states (specifically in PD) is far from understood. Furthermore, the etiological factors responsible for triggering aggregation of this protein remain elusive. This review is an attempt to collate and present latest information on α-syn in relation to its structure, biochemistry and biophysics of aggregation in PD. Current advances in therapeutic efforts toward clearing the pathogenic α-syn via autophagy/lysosomal flux are also reviewed and reported.
| S-EPMC8194081 | biostudies-literature
Project description:Parkinson's disease is the most common neurodegenerative movement disorder. It arises as a result of neuronal cell death in specific brain regions, notably the substantia nigra pars compacta, and is characterized by the accumulation of α-synuclein in these brain regions. Current pharmacological therapies alleviate the motor symptoms of the disease and are particularly effective in the early stages of the disease. Ongoing drug development efforts focus on disease-modifying strategies that aim to halt or slow disease progression. In this review, we explore a number of emerging disease-modifying strategies with a focus on direct and indirect targeting of α-synuclein dysfunction. We summarize newer classes of small molecules and biological agents intended to attenuate protein aggregation or to target enzymes that may increase the degradation of the pathogenic forms of α-synuclein. Finally, we discuss emerging strategies that are demonstrating the potential for disease modification at the preclinical stage.
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Project description:Aberrant secretion and accumulation of α-synuclein (α-Syn) as well as the loss of parkin function are associated with the pathogenesis of Parkinson's disease (PD). Our previous study suggested a functional interaction between those two proteins, showing that the extracellular α-Syn evoked post-translational modifications of parkin, leading to its autoubiquitination and degradation. While parkin plays an important role in mitochondrial biogenesis and turnover, including mitochondrial fission/fusion as well as mitophagy, the involvement of parkin deregulation in α-Syn-induced mitochondrial damage is largely unknown. In the present study, we demonstrated that treatment with exogenous α-Syn triggers mitochondrial dysfunction, reflected by the depolarization of the mitochondrial membrane, elevated synthesis of the mitochondrial superoxide anion, and a decrease in cellular ATP level. At the same time, we observed a protective effect of parkin overexpression on α-Syn-induced mitochondrial dysfunction. α-Syn-dependent disturbances of mitophagy were also shown to be directly related to reduced parkin levels in mitochondria and decreased ubiquitination of mitochondrial proteins. Also, α-Syn impaired mitochondrial biosynthesis due to the parkin-dependent reduction of PGC-1α protein levels. Finally, loss of parkin function as a result of α-Syn treatment induced an overall breakdown of mitochondrial homeostasis that led to the accumulation of abnormal mitochondria. These findings may thus provide the first compelling evidence for the direct association of α-Syn-mediated parkin depletion to impaired mitochondrial function in PD. We suggest that improvement of parkin function may serve as a novel therapeutic strategy to prevent mitochondrial impairment and neurodegeneration in PD (thereby slowing the progression of the disease).
| S-EPMC7943853 | biostudies-literature
Project description:Parkinson's disease (PD) is a progressive brain disorder that interferes with activities of normal life. The main pathological feature of this disease is the loss of more than 80% of dopamine-producing neurons in the substantia nigra (SN). Dopaminergic neuronal cell death occurs when intraneuronal, insoluble, aggregated proteins start to form Lewy bodies (LBs), the most important component of which is a protein called α-synuclein (α-syn). α-Syn structurally contains hexameric repeats of 11 amino acids, which are characteristic of apolipoproteins and thus α-syn can also be considered an apolipoprotein. Moreover, apolipoproteins seem to be involved in the incidence and development of PD. Some apolipoproteins such as ApoD have a neuroprotective role in the brain. In PD, apoD levels increase in glial cells surrounding dopaminergic cells. However, elevated levels of some other apolipoproteins such as ApaA1 and ApoE are reported as a vulnerability factor of PD. At present, when a clinical diagnosis of PD is made, based on symptoms such as shaking, stiff muscles and slow movement, serious damage has already been done to nerve cells of the SN. The diagnosis of PD in its earlier stages, before this irreversible damage, would be of enormous benefit for future treatment strategies designed to slow or halt the progression of PD. This review presents the roles of apolipoproteins and α-syn in PD and how some of them could potentially be used as biomarkers for PD.
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Project description:Parkinson's disease, neuropathologically defined by the aggregation of α-synuclein, is characterized by neuropsychiatric symptoms such as depression and anxiety preceding the onset of motor symptoms. A loss of serotonergic neurons or their projections into the hippocampus and alterations in serotonin release may be linked to these symptoms. Here, we investigate the effect of human A53T α-synuclein on serotonergic neurons using 12-months-old transgenic mice. We detected human α-synuclein in the perikarya of brainstem median and dorsal raphe neurons as well as in serotonergic fibers in the hippocampus. Despite intracellular α-synuclein accumulation there was no loss of serotonergic neurons in dorsal and median raphe nuclei of A53T α-synuclein mice. However, serotonin levels were significantly reduced in the brainstem. In addition, serotonergic fiber density in the dorsal dentate gyrus was significantly less dense in transgenic mice. Interestingly, we detected a significantly compromised increase in doublecortin+ neuroblasts after chronic treatment with fluoxetine at the site of reduced serotonergic innervation, the infrapyramidal blade of the dorsal dentate gyrus in A53T α-synuclein mice. This suggests that α-synuclein affects serotonergic projections in a spatially distinct pattern within the hippocampus thereby influencing the response to antidepressant treatment.
| S-EPMC4943922 | biostudies-literature
Project description:Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscore the role of α-Syn's mitochondrial localization in inducing TOM40 degradation. Parkinson's Disease related etiological factors, such as 6-hydroxy dopamine or ROS/metal ions stress, which promote α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.
| S-EPMC10925433 | biostudies-literature
Project description:An intrinsically disordered neuronal protein α-synuclein (αSyn) is known to cause mitochondrial dysfunction, contributing to loss of dopaminergic neurons in Parkinson's disease. Through yet poorly defined mechanisms, αSyn crosses mitochondrial outer membrane and targets respiratory complexes leading to bioenergetics defects. Here, using neuronally differentiated human cells overexpressing wild-type αSyn, we show that the major metabolite channel of the outer membrane, the voltage-dependent anion channel (VDAC), is a pathway for αSyn translocation into the mitochondria. Importantly, the neuroprotective cholesterol-like synthetic compound olesoxime inhibits this translocation. By applying complementary electrophysiological and biophysical approaches, we provide mechanistic insights into the interplay between αSyn, VDAC, and olesoxime. Our data suggest that olesoxime interacts with VDAC β-barrel at the lipid-protein interface thus hindering αSyn translocation through the VDAC pore and affecting VDAC voltage gating. We propose that targeting αSyn translocation through VDAC could represent a key mechanism for the development of new neuroprotective strategies.
| S-EPMC7244372 | biostudies-literature
Project description:Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3' region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3' region of SNCA. The four SNPs were in high LD (r(2) > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3' haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P-value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P-value = 0.0004). The 3' haplotype was also associated with disease (OR = 1.29; empirical P-value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3' region of SNCA convey an increased risk for PD.
| S-EPMC3397145 | biostudies-literature
Project description:Parkinson's disease (PD), a neurodegenerative disorder characterized by distinct aging-independent loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region urging toward neuronal loss. Over the decade, various key findings from clinical perspective to molecular pathogenesis have aided in understanding the genetics with assorted genes related with PD. Subsequently, several pathways have been incriminated in the pathogenesis of PD, involving mitochondrial dysfunction, protein aggregation, and misfolding. On the other hand, the sporadic form of PD cases is found with no genetic linkage, which still remain an unanswered question? The exertion in ascertaining vulnerability factors in PD considering the genetic factors are to be further dissevered in the forthcoming decades with advancement in research studies. One of the major proponents behind the prognosis of PD is the pathogenic transmutation of aberrant alpha-synuclein protein into amyloid fibrillar structures, which actuates neurodegeneration. Alpha-synuclein, transcribed by SNCA gene is a neuroprotein found predominantly in brain. It is implicated in the modulation of synaptic vesicle transport and eventual release of neurotransmitters. Due to genetic mutations and other elusive factors, the alpha-synuclein misfolds into its amyloid form. Therefore, this review aims in briefing the molecular understanding of the alpha-synuclein associated with PD.
| S-EPMC8558257 | biostudies-literature