scholarly journals An Emerging Role for Phosphoinositides in the Pathophysiology of Parkinson’s Disease

2021 ◽  
pp. 1-25
Author(s):  
Meir Schechter ◽  
Ronit Sharon
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Membrane Trafficking ◽  
Membrane Phospholipid ◽  
Genetic Mutations ◽  
Interacting Proteins ◽  
Data Support ◽  
Genes Encoding ◽  
Associated Proteins ◽  
Vesicular Membrane

Recent data support an involvement of defects in homeostasis of phosphoinositides (PIPs) in the pathophysiology of Parkinson’s disease (PD). Genetic mutations have been identified in genes encoding for PIP-regulating and PIP-interacting proteins, that are associated with familial and sporadic PD. Many of these proteins are implicated in vesicular membrane trafficking, mechanisms that were recently highlighted for their close associations with PD. PIPs are phosphorylated forms of the membrane phospholipid, phosphatidylinositol. Their composition in the vesicle’s membrane of origin, as well as membrane of destination, controls vesicular membrane trafficking. We review the converging evidence that points to the involvement of PIPs in PD. The review describes PD- and PIP-associated proteins implicated in clathrin-mediated endocytosis and autophagy, and highlights the involvement of α-synuclein in these mechanisms.

scholarly journals Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Muhammad Aslam ◽  
Nirosiya Kandasamy ◽  
Anwar Ullah ◽  
Nagarajan Paramasivam ◽  
Mehmet Ali Öztürk ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Rare Variants ◽  
Alpha Synuclein ◽  
Younger Age ◽  
Targeted Treatments ◽  
Genes Encoding ◽  
Rare Genetic Variants

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

Smoking, genes encoding dopamine pathway and risk for Parkinson's disease

2010 ◽  
Vol 482 (1) ◽  
pp. 31-34 ◽  
Author(s):  
Zhuqin Gu ◽  
Xiuli Feng ◽  
Xiumin Dong ◽  
Piu Chan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genes Encoding

Parkinson's disease genetic mutations increase cell susceptibility to stress: Mutant α-synuclein enhances H2O2- and Sin-1-induced cell death

2007 ◽  
Vol 28 (11) ◽  
pp. 1709-1717 ◽  
Author(s):  
Haibing Jiang ◽  
Yen-Ching Wu ◽  
Masayuki Nakamura ◽  
Yideng Liang ◽  
Yuji Tanaka ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Genetic Mutations

scholarly journals Explorative Combined Lipid and Transcriptomic Profiling of Substantia Nigra and Putamen in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1966 ◽  
Author(s):  
Helena Xicoy ◽  
Jos F. Brouwers ◽  
Bé Wieringa ◽  
Gerard J. M. Martens
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Molecular Mechanisms ◽  
Lipid Analysis ◽  
Dorsal Striatum ◽  
Receptor Subtype ◽  
Lipid Profiling ◽  
New Genes ◽  
Genes Encoding

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons from the substantia nigra (SN) that project to the dorsal striatum (caudate-putamen). To better understand the molecular mechanisms underlying PD, we performed combined lipid profiling and RNA sequencing of SN and putamen samples from PD patients and age-matched controls. SN lipid analysis pointed to a neuroinflammatory component and included elevated levels of the endosomal lipid Bis (Monoacylglycero)Phosphate 42:8, while two of the three depleted putamen lipids were saturated sphingomyelin species. Remarkably, we observed gender-related differences in the SN and putamen lipid profiles. Transcriptome analysis revealed that the top-enriched pathways among the 354 differentially expressed genes (DEGs) in the SN were “protein folding” and “neurotransmitter transport”, and among the 261 DEGs from putamen “synapse organization”. Furthermore, we identified pathways, e.g., “glutamate signaling”, and genes, encoding, e.g., an angiotensin receptor subtype or a proprotein convertase, that have not been previously linked to PD. The identification of 33 genes that were common among the SN and putamen DEGs, which included the α-synuclein paralog β-synuclein, may contribute to the understanding of general PD mechanisms. Thus, our proof-of-concept data highlights new genes, pathways and lipids that have not been explored before in the context of PD.

scholarly journals Extracellular Vesicles in Alzheimer’s and Parkinson’s Disease: Small Entities with Large Consequences

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2485
Author(s):  
Charysse Vandendriessche ◽  
Arnout Bruggeman ◽  
Caroline Van Cauwenberghe ◽  
Roosmarijn E. Vandenbroucke
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Extracellular Vesicles ◽  
Neurodegenerative Disorders ◽  
Neuronal Damage ◽  
Protein Aggregates ◽  
Pathological Changes ◽  
Associated Proteins ◽  
The Brain

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are incurable, devastating neurodegenerative disorders characterized by the formation and spreading of protein aggregates throughout the brain. Although the exact spreading mechanism is not completely understood, extracellular vesicles (EVs) have been proposed as potential contributors. Indeed, EVs have emerged as potential carriers of disease-associated proteins and are therefore thought to play an important role in disease progression, although some beneficial functions have also been attributed to them. EVs can be isolated from a variety of sources, including biofluids, and the analysis of their content can provide a snapshot of ongoing pathological changes in the brain. This underlines their potential as biomarker candidates which is of specific relevance in AD and PD where symptoms only arise after considerable and irreversible neuronal damage has already occurred. In this review, we discuss the known beneficial and detrimental functions of EVs in AD and PD and we highlight their promising potential to be used as biomarkers in both diseases.

scholarly journals Membrane Trafficking Illuminates a Path to Parkinson’s Disease

2017 ◽  
Vol 242 (1) ◽  
pp. 63-76 ◽  
Author(s):  
Takafumi Hasegawa ◽  
Naoto Sugeno ◽  
Akio Kikuchi ◽  
Toru Baba ◽  
Masashi Aoki
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Membrane Trafficking
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