scholarly journals The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 804
Author(s):  
Luca Magistrelli ◽  
Elena Contaldi ◽  
Cristoforo Comi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Neuronal Degeneration ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Main Component ◽  
The Impact

Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.

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 Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1333
Author(s):  
Maxime Teixeira ◽  
Razan Sheta ◽  
Walid Idi ◽  
Abid Oueslati
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Lewy Bodies ◽  
Cellular Membrane ◽  
Degradation Pathway ◽  
Alpha Synuclein ◽  
Potential Interaction ◽  
Abnormal Accumulation ◽  
Cellular Components

Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders.

scholarly journals Alpha-synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

Biology Open ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. bio054338
Author(s):  
Anila Iqbal ◽  
Marta Baldrighi ◽  
Jennifer N. Murdoch ◽  
Angeleen Fleming ◽  
Christopher J. Wilkinson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intracellular Transport ◽  
Neuronal Cell Death ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Cell Types ◽  
Alpha Synuclein ◽  
Microtubule Network ◽  
Main Component

ABSTRACTProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organise the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

scholarly journals When Friendship Turns Sour: Effective Communication Between Mitochondria and Intracellular Organelles in Parkinson's Disease

2020 ◽  
Vol 8 ◽  
Author(s):  
Tsu-Kung Lin ◽  
Kai-Jung Lin ◽  
Kai-Lieh Lin ◽  
Chia-Wei Liou ◽  
Shang-Der Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stress Responses ◽  
Redox Homeostasis ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Physical Contact ◽  
Substantia Nigra Pars Compacta ◽  
Intracellular Organelles ◽  
Pleiotropic Functions

Parkinson's disease (PD) is a complex neurodegenerative disease with pathological hallmarks including progressive neuronal loss from the substantia nigra pars compacta and α-synuclein intraneuronal inclusions, known as Lewy bodies. Although the etiology of PD remains elusive, mitochondrial damage has been established to take center stage in the pathogenesis of PD. Mitochondria are critical to cellular energy production, metabolism, homeostasis, and stress responses; the association with PD emphasizes the importance of maintenance of mitochondrial network integrity. To accomplish the pleiotropic functions, mitochondria are dynamic not only within their own network but also in orchestrated coordination with other organelles in the cellular community. Through physical contact sites, signal transduction, and vesicle transport, mitochondria and intracellular organelles achieve the goals of calcium homeostasis, redox homeostasis, protein homeostasis, autophagy, and apoptosis. Herein, we review the finely tuned interactions between mitochondria and surrounding intracellular organelles, with focus on the nucleus, endoplasmic reticulum, Golgi apparatus, peroxisomes, and lysosomes. Participants that may contribute to the pathogenic mechanisms of PD will be highlighted in this review.

scholarly journals Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease

2020 ◽  
Vol 14 ◽  
Author(s):  
Niklas Reich ◽  
Christian Hölscher
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Alpha Synuclein ◽  
Acylated Ghrelin ◽  
Therapeutic Benefits ◽  
Term Administration ◽  
The Impact ◽  
Impaired Neurogenesis

Much thought has been given to the impact of Amyloid Beta, Tau and Alpha-Synuclein in the development of Alzheimer's disease (AD) and Parkinson's disease (PD), yet the clinical failures of the recent decades indicate that there are further pathological mechanisms at work. Indeed, besides amyloids, AD and PD are characterized by the culminative interplay of oxidative stress, mitochondrial dysfunction and hyperfission, defective autophagy and mitophagy, systemic inflammation, BBB and vascular damage, demyelination, cerebral insulin resistance, the loss of dopamine production in PD, impaired neurogenesis and, of course, widespread axonal, synaptic and neuronal degeneration that leads to cognitive and motor impediments. Interestingly, the acylated form of the hormone ghrelin has shown the potential to ameliorate the latter pathologic changes, although some studies indicate a few complications that need to be considered in the long-term administration of the hormone. As such, this review will illustrate the wide-ranging neuroprotective properties of acylated ghrelin and critically evaluate the hormone's therapeutic benefits for the treatment of AD and PD.

scholarly journals A Case of Parkinson’s Disease with No Lewy Body Pathology due to a Homozygous Exon Deletion in Parkin

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Krisztina Kunszt Johansen ◽  
Sverre Helge Torp ◽  
Matthew J. Farrer ◽  
Emil K. Gustavsson ◽  
Jan O. Aasly
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Diagnostic Criteria ◽  
Lewy Body ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Homozygous Deletion ◽  
Substantia Nigra Pars Compacta ◽  
Lewy Body Pathology ◽  
Deep Brain

Parkinson’s disease (PD) is a clinical diagnosis based on the presence of cardinal motor signs, good response to levodopa, and no other explanations of the syndrome. Earlier diagnostic criteria required autopsy for a definite diagnosis based on neuronal loss in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies and neurites. Here, we present a patient who developed parkinsonism around the age of 20, with an excellent response to levodopa who, at age 65, received bilateral STN deep brain stimulation (DBS). The patient died at age 79. The autopsy showed severe neuronal loss in the SN without any Lewy bodies in the brainstem or in the hemispheres. Genetic screening revealed a homozygous deletion of exon 3-4 in the Parkin gene. In this case report we discuss earlier described pathological findings in Parkin cases without Lewy body pathology, the current diagnostic criteria for PD, and their clinical relevance.

scholarly journals Gastrointestinal Biopsies for the Diagnosis of Alpha-Synuclein Pathology in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Maria Graciela Cersosimo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Biopsy Material ◽  
Autopsy Examination ◽  
Colon And Rectum ◽  
Rostrocaudal Gradient

The diagnosis of Parkinson’s disease (PD) relies on clinical features whereas pathological confirmation is only possible with autopsy examination. The neuropathological hallmarks of PD are neuronal loss and the presence of inclusions termed Lewy bodies/neurites in affected regions. A major component of these inclusions is phosphorylated alpha-synuclein (α-SYN) protein. There is evidence thatα-SYN pathology is widely distributed outside the central nervous system in patients with PD. The gastrointestinal tract is importantly affected byα-SYN containing inclusions and typically there is a rostrocaudal gradient for the distribution of the pathology. The highest amounts of Lewy bodies/neurites are found at the submandibular gland together with the lower esophagus and the lowest amounts are found in the rectum. Autopsy findings prompted research aimed at achieving in vivo pathological diagnosis of PD by demonstrating the presence ofα-SYN pathology in biopsy material of these peripheral accessible tissues. So far, biopsy studies of the gut have demonstrated the presence ofα-SYN pathology in the salivary glands, stomach, duodenum, colon, and rectum. Further research is necessary in order to determine which are the most sensitive targets for in vivoα-SYN pathology detection and the safest techniques for these approaches in patients with PD.

scholarly journals Alpha-Synuclein in Parkinson’s Disease: From Pathogenetic Dysfunction to Potential Clinical Application

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Lingjia Xu ◽  
Jiali Pu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Current Knowledge ◽  
Point Mutations ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Lewy Neurites

Parkinson’s disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure. Progressive dopaminergic neuronal cell loss in the substantia nigra pars compacta and widespread aggregation of theα-synuclein protein (encoded by theSNCAgene) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson’s disease. TheSNCAgene has undergone gene duplications, triplications, and point mutations. However, the specific mechanism ofα-synuclein in Parkinson’s disease remains obscure. Recent research showed that variousα-synuclein oligomers, pathological aggregation, and propagation appear to be harmful in certain areas in Parkinson’s disease patients. This review summarizes our current knowledge of the pathogenetic dysfunction ofα-synuclein associated with Parkinson’s disease and highlights current approaches that seek to develop this protein as a possible diagnostic biomarker and therapeutic target.

scholarly journals MicroRNAs: Game Changers in the Regulation of α-Synuclein in Parkinson’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Liang Zhao ◽  
Zhiqin Wang
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
Noncoding Rnas ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Substantia Nigra Pars Compacta ◽  
Common Neurodegenerative Disorder

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Its neuropathological hallmarks include neuronal loss in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies containing aggregates of α-synuclein (α-syn). An imbalance between the rates of α-syn synthesis, aggregation, and clearance can result in abnormal α-syn levels and contribute to the pathogenesis of PD. MicroRNAs (miRNAs) are endogenous single-stranded noncoding RNAs (∼22 nucleotides) that have recently emerged as key posttranscriptional regulators of gene expression. In this review, we summarize the functions of miRNAs that directly target α-syn. We also review miRNAs that indirectly impact α-syn levels or toxicity through different pathways, including those involved in the clearance of α-syn and neuroinflammation.

scholarly journals Dual Roles of Microglia in the Basal Ganglia in Parkinson’s Disease

2021 ◽  
Vol 22 (8) ◽  
pp. 3907
Author(s):  
Mohammed E. Choudhury ◽  
Yuka Kigami ◽  
Junya Tanaka
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Substantia Nigra ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Therapeutic Interventions ◽  
Substantia Nigra Pars Compacta ◽  
Synapse Elimination ◽  
Dual Roles

With the increasing age of the population, the incidence of Parkinson’s disease (PD) has increased exponentially. The development of novel therapeutic interventions requires an understanding of the involvement of senescent brain cells in the pathogenesis of PD. In this review, we highlight the roles played by microglia in the basal ganglia in the pathophysiological processes of PD. In PD, dopaminergic (DAergic) neuronal degeneration in the substantia nigra pars compacta (SNc) activates the microglia, which then promote DAergic neuronal degeneration by releasing potentially neurotoxic factors, including nitric oxide, cytokines, and reactive oxygen species. On the other hand, microglia are also activated in the basal ganglia outputs (the substantia nigra pars reticulata and the globus pallidus) in response to excess glutamate released from hyperactive subthalamic nuclei-derived synapses. The activated microglia then eliminate the hyperactive glutamatergic synapses. Synapse elimination may be the mechanism underlying the compensation that masks the appearance of PD symptoms despite substantial DAergic neuronal loss. Microglial senescence may correlate with their enhanced neurotoxicity in the SNc and the reduced compensatory actions in the basal ganglia outputs. The dual roles of microglia in different basal ganglia regions make it difficult to develop interventions targeting microglia for PD treatment.

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