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 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 Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson's Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 206 ◽  
Author(s):  
Tsung-Hsun Hsieh ◽  
Chi-Wei Kuo ◽  
Kai-Hsuan Hsieh ◽  
Meng-Jyh Shieh ◽  
Chih-Wei Peng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Coordination ◽  
Dopamine Neurons ◽  
Motor Symptoms ◽  
Neuroprotective Effects ◽  
Motor Functions ◽  
Term Administration ◽  
Nigrostriatal Dopamine Neurons

Parkinson’s disease (PD) is one of the common long-term degenerative disorders that primarily affect motor systems. Gastrointestinal (GI) symptoms are common in individuals with PD and often present before motor symptoms. It has been found that gut dysbiosis to PD pathology is related to the severity of motor and non-motor symptoms in PD. Probiotics have been reported to have the ability to improve the symptoms related to constipation in PD patients. However, the evidence from preclinical or clinical research to verify the beneficial effects of probiotics for the motor functions in PD is still limited. An experimental PD animal model could be helpful in exploring the potential therapeutic strategy using probiotics. In the current study, we examined whether daily and long-term administration of probiotics has neuroprotective effects on nigrostriatal dopamine neurons and whether it can further alleviate the motor dysfunctions in PD mice. Transgenic MitoPark PD mice were chosen for this study and the effects of daily probiotic treatment on gait, beam balance, motor coordination, and the degeneration levels of dopaminergic neurons were identified. From the results, compared with the sham treatment group, we found that the daily administration of probiotics significantly reduced the motor impairments in gait pattern, balance function, and motor coordination. Immunohistochemically, a tyrosine hydroxylase (TH)-positive cell in the substantia nigra was significantly preserved in the probiotic-treated PD mice. These results showed that long-term administration of probiotics has neuroprotective effects on dopamine neurons and further attenuates the deterioration of motor dysfunctions in MitoPark PD mice. Our data further highlighted the promising possibility of the potential use of probiotics, which could be the relevant approach for further application on human PD subjects.

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 Interventional Influence of the Intestinal Microbiome Through Dietary Intervention and Bowel Cleansing Might Improve Motor Symptoms in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 376 ◽  
Author(s):  
Tobias Hegelmaier ◽  
Marco Lebbing ◽  
Alexander Duscha ◽  
Laura Tomaske ◽  
Lars Tönges ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gut Microbiome ◽  
Dietary Intervention ◽  
Therapeutic Option ◽  
Vegetarian Diet ◽  
Alpha Synuclein ◽  
Intestinal Microbiome ◽  
Bowel Cleansing ◽  
The Impact

The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson’s disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with a better understanding of the intestinal microbiome, a link to the misfolding and spread of alpha-synuclein via inflammatory processes within the gut is discussed. In a case-control study, we assessed the gut microbiome of 54 PD patients and 32 healthy controls (HC). Additionally, we tested in this proof-of-concept study whether dietary intervention alone or additional physical colon cleaning may lead to changes of the gut microbiome in PD. 16 PD patients underwent a well-controlled balanced, ovo-lacto vegetarian diet intervention including short fatty acids for 14 days. 10 of those patients received additional treatment with daily fecal enema over 8 days. Stool samples were collected before and after 14 days of intervention. In comparison to HC, we could confirm previously reported PD associated microbiome changes. The UDPRS III significantly improved and the levodopa-equivalent daily dose decreased after vegetarian diet and fecal enema in a one-year follow-up. Additionally, we observed a significant association between the gut microbiome diversity and the UPDRS III and the abundance of Ruminococcaceae. Additionally, the abundance of Clostridiaceae was significantly reduced after enema. Dietary intervention and bowel cleansing may provide an additional non-pharmacologic therapeutic option for PD patients.

scholarly journals Alpha-Synuclein in the Gastrointestinal Tract as a Potential Biomarker for Early Detection of Parkinson’s Disease

2020 ◽  
Vol 21 (22) ◽  
pp. 8666
Author(s):  
Dominika Fricova ◽  
Jana Harsanyiova ◽  
Alzbeta Kralova Trancikova
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Clinical Symptoms ◽  
Neuronal Degeneration ◽  
Alpha Synuclein ◽  
Diagnostic Methods ◽  
Alternative Methods ◽  
Peripheral Tissues ◽  
Potential Biomarker

The primary pathogenesis associated with Parkinson’s disease (PD) occurs in peripheral tissues several years before the onset of typical motor symptoms. Early and reliable diagnosis of PD could provide new treatment options for PD patients and improve their quality of life. At present, however, diagnosis relies mainly on clinical symptoms, and definitive diagnosis is still based on postmortem pathological confirmation of dopaminergic neuronal degeneration. In addition, the similarity of the clinical, cognitive, and neuropathological features of PD with other neurodegenerative diseases calls for new biomarkers, suitable for differential diagnosis. Alpha-synuclein (α-Syn) is a potential PD biomarker, due to its close connection with the pathogenesis of the disease. Here we summarize the currently available information on the possible use of α-Syn as a biomarker of early stages of PD in gastrointestinal (GI) tissues, highlight its potential to distinguish PD and other neurodegenerative diseases, and suggest alternative methods (primarily developed for other tissue analysis) that could improve α-Syn detection procedures or diagnostic methods in general.

scholarly journals GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2215
Author(s):  
Silvia Cerri ◽  
Cristina Ghezzi ◽  
Gerardo Ongari ◽  
Stefania Croce ◽  
Micol Avenali ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Fibroblast Cell ◽  
Alpha Synuclein ◽  
Gene Encoding ◽  
Gba Gene ◽  
The Impact ◽  
Gba Mutations

Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal–lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD.

scholarly journals Alpha-synuclein levels modulate seeding and aggregation in cultured cells

2021 ◽  
Author(s):  
Eftychia Vasili ◽  
Antonio Dominguez-Meijide ◽  
Manuel Flores-León ◽  
Mohammed Al-Azzani ◽  
Angeliki Kanellidi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Stable Cell Lines ◽  
The Impact

Abstract Background Parkinson's disease is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha-synuclein in intraneuronal inclusions known as Lewy bodies and Lewy neurites. Multiple studies strongly implicate the levels of alpha-synuclein as a major risk factor for the onset and progression of Parkinson’s disease. alpha-Synuclein pathology spreads progressively throughout interconnected brain regions but the precise molecular mechanisms underlying alpha-synuclein spreading and accumulation remain obscure. Methods Here, using stable cell lines expressing alpha-synuclein, we examined the correlation between endogenous alpha-synuclein levels and the seeding propensity by exogenous alpha-synuclein pre-formed fibrils. We applied biochemical approaches and imaging methods in stable cell lines expressing alpha-synuclein and in primary neurons to determine the impact of alpha-synuclein expression levels on seeding and aggregation. Results Our results indicate that alpha-synuclein levels define the pattern and severity of aggregation and the extent of p-alpha-synuclein deposition, likely explaining the selective vulnerability of different cell types in synucleinopathies. Conclusions The elucidation of the cellular processes involved in the pathological aggregation of alpha-synuclein will enable the identification of novel targets and the development of therapeutic strategies for Parkinson's disease and other synucleinopathies.

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.

Parkinsonism and Parkinson's disease associated with long-term administration of sertraline

2001 ◽  
Vol 26 (2) ◽  
pp. 111-112 ◽  
Author(s):  
M. A. Pina Latorre ◽  
P. J. Modrego ◽  
F. Rodilla ◽  
C. Catalan ◽  
M. Calvo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Term Administration
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