scholarly journals Unexpected Implication of SRP and AGO2 in Parkinson’s Disease: Involvement in Alpha-Synuclein Biogenesis

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2792
Author(s):  
Sarah Hernandez ◽  
Elena Tikhonova ◽  
Kristen Baca ◽  
Fanpeng Zhao ◽  
Xiongwei Zhu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Protein Quality ◽  
Neurodegenerative Disorder ◽  
Signal Sequence ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Cytoplasmic Inclusions ◽  
Hydrophobic Domain

Parkinson’s disease (PD) is a neurodegenerative disorder classified by the loss of dopaminergic neurons in the substantia nigra pars compacta, the region of the brain that is responsible for motor control. Surviving neurons in this region contain aggregated protein alpha-Synuclein (αSyn) in the form of cytoplasmic inclusions, referred to as Lewy bodies. Changes in αSyn expression are also associated with PD and its progression. Previously, we demonstrated that signal recognition particle (SRP) and Argonaute 2 (AGO2) proteins are involved in protein quality control at the ribosome during translation. We also demonstrated that SRP has an mRNA protection function in addition to a protein targeting function, thus controlling mRNA and protein expression. In this study, we tested involvement of these factors in αSyn biogenesis. We hypothesize that loss of these factors may interfere with αSyn expression, and subsequently, be associated with PD. Using depletion assays in human cell culture and analysis of these proteins in the brains of deceased PD patients, we demonstrate that SRP and AGO2 are involved in the control of αSyn expression and AGO2 has reduced expression in PD. We show for the first time that SRP is involved in mRNA protection of αSyn, a protein that does not have a signal sequence or transmembrane span. Our findings suggest that SRP may interact with a hydrophobic domain in the middle of αSyn during translation. Understanding the molecular mechanisms controlling αSyn biogenesis in cells is vital to developing preventative therapies against PD.

scholarly journals Parkinson's disease and mitophagy: an emerging role for LRRK2

2021 ◽  
Author(s):  
Francois Singh ◽  
Ian G. Ganley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Muscle Stiffness ◽  
Substantia Nigra Pars Compacta ◽  
Common Mutation ◽  
Common Denominator

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

Effect of Cabergoline on Cognitive Impairments in Transgenic Drosophila Model of Parkinson’s Disease

2020 ◽  
Vol 17 (10) ◽  
pp. 1261-1269
Author(s):  
Yasir Hasan Siddique ◽  
Rahul ◽  
Mantasha Idrisi ◽  
Mohd. Shahid
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Cognitive Impairments ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Positive Interaction ◽  
Drosophila Model ◽  
Transgenic Drosophila

Background: Parkinson’s disease is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta. Introduction: The effects of alpha synuclein, parkin mutation and pharmacological agents have been studied in the Drosophila model. Methods: The effect of cabergoline was studied on the cognitive impairments exhibited by the transgenic Drosophila expressing human alpha-synuclein in the neurons. The PD flies were allowed to feed on the diet having 0.5, 1 and 1.5 μM of cabergoline. Results and Discussion: The exposure of cabergoline not only showed a dose-dependent significant delay in the cognitive impairments but also prevented the loss of dopaminergic neurons. Molecular docking studies showed the positive interaction between cabergoline and alpha-synuclein. Conclusion: The results suggest a protective effect of cabergoline against the cognitive impairments.

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 Alpha-synuclein promotes dopaminergic neuron death in Parkinson’s disease through microglial and NLRP3 activation

2020 ◽  
Vol 6 (2) ◽  
Author(s):  
Sarah Klein
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nlrp3 Inflammasome ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficits ◽  
Inflammasome Activation ◽  
Neuron Death ◽  
Nlrp3 Inflammasome Activation

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that involves the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). After neuronal death, the subsequent reduction of dopamine levels in the brain induces motor deficits characteristic of this hypokinetic disorder. Although there is currently no known cause of PD, alpha-synuclein appears to have a prominent role in both microglial and NLRP3 inflammasome activation. The consequential release of the pro-inflammatory cytokine interleukin-1β (IL-1β) has been demonstrated to be responsible for neuroinflammation and neurodegeneration in PD. The present review highlights the role of alpha-synuclein aggregates in Parkinson’s disease pathogenesis. The PD alpha-synuclein preformed fibril (PFF) animal model permits the specific targeting of alpha-synuclein-mediated microglial and NLRP3 inflammasome activation in newly designed therapies. Studies using this model suggest MCC950 and its analogs as a potential new treatment to prevent neurodegeneration in Parkinson’s disease.

scholarly journals Parkinson’s Disease-Related Genes and Lipid Alteration

2021 ◽  
Vol 22 (14) ◽  
pp. 7630
Author(s):  
Milena Fais ◽  
Antonio Dore ◽  
Manuela Galioto ◽  
Grazia Galleri ◽  
Claudia Crosio ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Clinical Manifestations ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Protein Clearance ◽  
Genetic And Environmental Factors

Parkinson’s disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5–1% among those aged 65–70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration—for instance, alpha-synuclein accumulation—and finally neuronal death.

scholarly journals Endogenous Levels of Alpha-Synuclein Modulate Seeding and Aggregation in Cultured Cells

2022 ◽  
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

AbstractParkinson’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 the seeding of alpha-synuclein aggregation are still unclear. 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 preformed 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 levels on seeding and aggregation. Our results indicate that the levels of alpha-synuclein 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. 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 Physiological and pathological functions of LRRK2: implications from substrate proteins

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Miho Araki ◽  
Genta Ito ◽  
Taisuke Tomita
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Motor Dysfunction ◽  
Substantia Nigra Pars Compacta ◽  
Rab Gtpases ◽  
Substrate Proteins

Leucine-rich repeat kinase 2 (LRRK2) encodes a 2527-amino acid (aa) protein composed of multiple functional domains, including a Ras of complex proteins (ROC)-type GTP-binding domain, a carboxyl terminal of ROC (COR) domain, a serine/threonine protein kinase domain, and several repeat domains. LRRK2 is genetically involved in the pathogenesis of both sporadic and familial Parkinson’s disease (FPD). Parkinson’s disease (PD) is the second most common neurodegenerative disorder, manifesting progressive motor dysfunction. PD is pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and the presence of intracellular inclusion bodies called Lewy bodies (LB) in the remaining neurons. As the most frequent PD-causing mutation in LRRK2, G2019S, increases the kinase activity of LRRK2, an abnormal increase in LRRK2 kinase activity is believed to contribute to PD pathology; however, the precise biological functions of LRRK2 involved in PD pathogenesis remain unknown. Although biochemical studies have discovered several substrate proteins of LRRK2 including Rab GTPases and tau, little is known about whether excess phosphorylation of these substrates is the cause of the neurodegeneration in PD. In this review, we summarize latest findings regarding the physiological and pathological functions of LRRK2, and discuss the possible molecular mechanisms of neurodegeneration caused by LRRK2 and its substrates.

scholarly journals Current Progress of Mitochondrial Quality Control Pathways Underlying the Pathogenesis of Parkinson’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Xue Jiang ◽  
Tao Jin ◽  
Haining Zhang ◽  
Jing Miao ◽  
Xiuzhen Zhao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Dynamics ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Toxic Metabolite ◽  
Mitochondrial Quality Control

Parkinson’s disease (PD), clinically characterized by motor and nonmotor symptoms, is a common progressive and multisystem neurodegenerative disorder, which is caused by both genetic and environmental risk factors. The main pathological features of PD are the loss of dopaminergic (DA) neurons and the accumulation of alpha-synuclein (α-syn) in the residual DA neurons in the substantia nigra pars compacta (SNpc). In recent years, substantial progress has been made in discovering the genetic factors of PD. In particular, a total of 19 PD-causing genes have been unraveled, among which some members have been regarded to be related to mitochondrial dysfunction. Mitochondria are key regulators of cellular metabolic activity and are critical for many important cellular processes including energy metabolism and even cell death. Their normal function is basically maintained by the mitochondrial quality control (MQC) mechanism. Accordingly, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a kind of neurotoxin, exerts its neurotoxic effects at least partially by producing its toxic metabolite, namely, 1-methyl-4-phenylpyridine (MPP+), which in turn causes mitochondrial dysfunction by inhibiting complex I and mimicking the key features of PD pathogenesis. This review focused on three main aspects of the MQC signaling pathways, that is, mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy; hence, it demonstrates in detail how genetic and environmental factors result in PD pathogenesis by interfering with MQC pathways, thereby hopefully contributing to the discovery of novel potential therapeutic targets for PD.

scholarly journals Endogenous Levels of Alpha-synuclein Modulate Seeding and Aggregation in Cultured Cells

2021 ◽  
Author(s):  
Eftychia Vasili ◽  
Antonio Dominguez-Meijide ◽  
Manuel Flores-Léon ◽  
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 the seeding of alpha-synuclein aggregation are still unclear.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 levels on seeding and aggregation. Results: Our results indicate that the levels of alpha-synuclein 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 Alpha-Synuclein Aggregation in Parkinson's Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
E. Srinivasan ◽  
G. Chandrasekhar ◽  
P. Chandrasekar ◽  
K. Anbarasu ◽  
A. S. Vickram ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Genetic Factors ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Vulnerability Factors ◽  
Alpha Synuclein Aggregation

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.

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