scholarly journals Familial Mutations and Post-translational Modifications of UCH-L1 in Parkinson’s Disease and Neurodegenerative Disorders

2016 ◽  
Author(s):  
Yun-Tzai Cloud Lee ◽  
Shang-Te Danny Hsu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorders ◽  
Lewy Bodies ◽  
Modern Society ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Inclusions ◽  
Biophysical Studies ◽  
The Impact

AbstractParkinson’s disease (PD) is one of the most common progressive neurodegenerative disorders in modern society. The disease involves many genetic risk factors as well as a sporadic pathogenesis that is age- and environment-dependent. Of particular interest is the formation of intra-neural fibrillar aggregates, namely Lewy bodies (LBs), the histological hallmark of PD, which results from aberrant protein homeostasis or misfolding that results in neurotoxicity. A better understanding of the molecular mechanism and composition of these cellular inclusions will help shed light on the progression of misfolding-associated neurodegenerative disorders. Ubiquitin carbonyl-terminal hydrolase L1 (UCH-L1) is found to co-aggregate with α-synuclein (αS), the major component of LBs. Several familial mutations of UCH-L1, namely p.Ile93Met (p.I93M), p.Glu7Ala (p.E7A), and p.Ser18Tyr (p.S18Y), are associated with PD and other neurodegenerative disorders. Here, we review recent progress and recapitulate the impact of PD-associated mutations of UCH-L1 in the context of their biological functions gleaned from biochemical and biophysical studies. Finally, we summarize the effect of these genetic mutations and post-translational modifications on the association of UCH-L1 and PD in terms of loss of cellular functions or gain of cellular toxicity.

scholarly journals Modulation of the Interactions Between α-Synuclein and Lipid Membranes by Post-translational Modifications

2021 ◽  
Vol 12 ◽  
Author(s):  
Rosie Bell ◽  
Michele Vendruscolo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lipid Membranes ◽  
Lewy Bodies ◽  
Lewy Neurites ◽  
Post Translational Modifications ◽  
Therapeutic Tools ◽  
Cellular Components ◽  
The Impact

Parkinson's disease is characterised by the presence in brain tissue of aberrant inclusions known as Lewy bodies and Lewy neurites, which are deposits composed by α-synuclein and a variety of other cellular components, including in particular lipid membranes. The dysregulation of the balance between lipid homeostasis and α-synuclein homeostasis is therefore likely to be closely involved in the onset and progression of Parkinson's disease and related synucleinopathies. As our understanding of this balance is increasing, we describe recent advances in the characterisation of the role of post-translational modifications in modulating the interactions of α-synuclein with lipid membranes. We then discuss the impact of these advances on the development of novel diagnostic and therapeutic tools for synucleinopathies.

scholarly journals The activities of LRRK2 and GCase are positively correlated in clinical biospecimens and experimental models of Parkinson’s disease

2021 ◽  
Author(s):  
Maria Kedariti ◽  
Emanuele Frattini ◽  
Pascale Baden ◽  
Susanna Cogo ◽  
Laura Civiero ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Experimental Models ◽  
Cellular Functions ◽  
Gene Encoding ◽  
Cellular Models ◽  
Lrrk2 Kinase ◽  
The Impact ◽  
Lrrk2 Kinase Activity

AbstractLRRK2 is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways and vesicle trafficking. Mutations in LRRK2 cause autosomal dominant forms of Parkinson’s disease (PD). Heterozygous mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we investigated GCase levels and activity in LRRK2 G2019S knockin mice, in clinical biospecimens from PD patients carrying this mutation and in patient-derived cellular models. In these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase.

scholarly journals Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

2018 ◽  
Author(s):  
Tim E. Moors ◽  
Christina A. Maat ◽  
Daniel Niedieker ◽  
Daniel Mona ◽  
Dennis Petersen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Distribution Patterns ◽  
Alpha Synuclein ◽  
Label Free ◽  
Post Translational Modifications ◽  
Sted Microscopy ◽  
C Terminus

AbstractPost-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

scholarly journals Presence of genetic polymorphisms may impact on predisposition to Parkinson’s disease

2021 ◽  
Author(s):  
Rubens Barbosa Rezende ◽  
Larissa Teodoro
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Risk ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Single Nucleotide ◽  
Asian Populations ◽  
Lrrk2 Gene ◽  
The Impact ◽  
Reduced Risk

Introduction: Parkinson’s disease (PD) is characterized by the degeneration and loss of dopaminergic neurons in the black substantia and the formation of Lewy bodies, thus being considered a neurodegenerative disease. Thus, the objective was to understand the impact of polymorphisms in the predisposition to PD. Methods: It’s a narrative review of literature in the PubMed and SciELO databases, using the descriptors: “Polymorphism, Single Nucleotide” and “Parkinson disease”, registered in DeCS/MeSH, and using the Boolean operator AND. The inclusion criteria were: complete articles and made available free of charge, published in English, Spanish and Portuguese, between 2016 and January 2021. Results: After the research, 167 publications were found and seven were included. The data from the first study indicate that the rs33949390 of the LRRK2 gene helps in predisposition to PD in Asian populations, mainly Chinese. The second study indicated that the NFE2L2 rs6721961 allele was linked to a reduced risk of PD. The third study found that the GSK3B rs1732170, STK11 rs8111699, SNCA rs356219 and FCHSD1 rs456998 polymorphisms were linked to a high risk of PD. The fourth study found that the SNCA variants rs7684318, rs356220, rs356203 and rs2736990 were linked to the disease and were at high risk of developing PD in the Mexican population. The fifth and sixth study are meta-analyzes, the fifth confirming the lower allele rs11558538 of HNMT is associated with a reduced risk of developing PD. And the sixth assumes a possible link between CCDC62 rs12817488 and the risk of PD in the Chinese population. Conclusion: However, the analyzed data indicate that the polymorphisms contributed to the susceptibility to PD, however further studies related to the polymorphisms and their relationship to PD are still needed for more ethnic groups, and thus early diagnosis is possible.

scholarly journals LRRK2 at the Crossroad of Aging and Parkinson’s Disease

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 505
Author(s):  
Eun-Mi Hur ◽  
Byoung Dae Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Onset ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Cellular Functions ◽  
Lewy Neurites ◽  
Clinical Presentations ◽  
Lrrk2 Gene ◽  
Cellular Dysfunction

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the widespread occurrence of proteinaceous inclusions known as Lewy bodies and Lewy neurites. The etiology of PD is still far from clear, but aging has been considered as the highest risk factor influencing the clinical presentations and the progression of PD. Accumulating evidence suggests that aging and PD induce common changes in multiple cellular functions, including redox imbalance, mitochondria dysfunction, and impaired proteostasis. Age-dependent deteriorations in cellular dysfunction may predispose individuals to PD, and cellular damages caused by genetic and/or environmental risk factors of PD may be exaggerated by aging. Mutations in the LRRK2 gene cause late-onset, autosomal dominant PD and comprise the most common genetic causes of both familial and sporadic PD. LRRK2-linked PD patients show clinical and pathological features indistinguishable from idiopathic PD patients. Here, we review cellular dysfunctions shared by aging and PD-associated LRRK2 mutations and discuss how the interplay between the two might play a role in PD pathologies.

scholarly journals Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson’s Disease: Roads to Biomarker Discovery

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1508
Author(s):  
Anna Picca ◽  
Flora Guerra ◽  
Riccardo Calvani ◽  
Roberta Romano ◽  
Hélio José Coelho-Júnior ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Protein Misfolding ◽  
Biomarker Discovery ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Lewy Neurites ◽  
Post Translational Modifications ◽  
Ubiquitin Proteasome

Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.

scholarly journals Rab27 GTPases regulate alpha-synuclein uptake, cell-to-cell transmission, and toxicity

2020 ◽  
Author(s):  
Rachel Underwood ◽  
Bing Wang ◽  
Aneesh Pathak ◽  
Laura Volpicelli-Daley ◽  
Talene A. Yacoubian
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Rab Gtpases ◽  
Double Knockout ◽  
The Impact

SUMMARYParkinson’s disease and Dementia with Lewy Bodies are two common neurodegenerative disorders marked by proteinaceous aggregates composed primarily of the protein α-synuclein. α-Synuclein is hypothesized to have prion-like properties, by which misfolded α-synuclein induces the pathological aggregation of endogenous α-synuclein and neuronal loss. Rab27a and Rab27b are two highly homologous Rab GTPases that regulate α-synuclein secretion, clearance, and toxicity in vitro. In this study, we tested the impact of Rab27a/b on the transmission of pathogenic α-synuclein. Double knockout of both Rab27 isoforms eliminated α-synuclein aggregation and neuronal toxicity in primary cultured neurons exposed to fibrillary α-synuclein. In vivo, Rab27 double knockout mice lacked fibril-induced α-synuclein inclusions, dopaminergic neuron loss, and behavioral deficits seen in wildtype mice with fibril-induced inclusions. Studies using AlexaFluor488-labeled α-synuclein fibrils revealed that Rab27a/b knockout prevented α-synuclein internalization without affecting bulk endocytosis. Rab27a/b knockout also blocked the cell-to-cell spread of α-synuclein pathology in multifluidic, multichambered devices. This study provides critical insight into the role of Rab GTPases in Parkinson’s disease and identifies Rab27s as key players in the progression of synucleinopathies.

scholarly journals Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease

2018 ◽  
Vol 115 (25) ◽  
pp. E5815-E5823 ◽  
Author(s):  
Qian Ren ◽  
Min Ma ◽  
Jun Yang ◽  
Risa Nonaka ◽  
Akihiro Yamaguchi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorders ◽  
Epoxide Hydrolase ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Soluble Epoxide Hydrolase ◽  
Postmortem Brain ◽  
Control Treatment ◽  
Increased Activity

Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder, and the deposition of specific protein aggregates of α-synuclein, termed Lewy bodies, is evident in multiple brain regions of PD patients. Although there are several available medications to treat PD symptoms, these medications do not prevent the progression of the disease. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with the pathogenesis of PD. Here we found that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity in the mouse striatum was attenuated by subsequent repeated administration of TPPU, a potent sEH inhibitor. Furthermore, deletion of the sEH gene protected against MPTP-induced neurotoxicity, while overexpression of sEH in the striatum significantly enhanced MPTP-induced neurotoxicity. Moreover, the expression of the sEH protein in the striatum from MPTP-treated mice or postmortem brain samples from patients with dementia of Lewy bodies (DLB) was significantly higher compared with control groups. Interestingly, there was a positive correlation between sEH expression and phosphorylation of α-synuclein in the striatum. Oxylipin analysis showed decreased levels of 8,9-epoxy-5Z,11Z,14Z-eicosatrienoic acid in the striatum of MPTP-treated mice, suggesting increased activity of sEH in this region. Interestingly, the expression of sEH mRNA in human PARK2 iPSC-derived neurons was higher than that of healthy control. Treatment with TPPU protected against apoptosis in human PARK2 iPSC-derived dopaminergic neurons. These findings suggest that increased activity of sEH in the striatum plays a key role in the pathogenesis of neurodegenerative disorders such as PD and DLB. Therefore, sEH may represent a promising therapeutic target for α-synuclein–related neurodegenerative disorders.

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