International Journal of Molecular Sciences

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18 pages, 3084 KiB

Open AccessArticle

The Impact of 90 Parkinson’s Disease-Risk Single Nucleotide Polymorphisms on Urinary Bis(monoacylglycerol)phosphate Levels in the Prodromal and PD Cohorts

by Shuai Fang, Priscilla Ann Hweek Lee, Zejian Wang and Bo Zhao

Int. J. Mol. Sci. 2024, 25(4), 2286; https://doi.org/10.3390/ijms25042286 - 14 Feb 2024

Viewed by 1545

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder with a prolonged prodromal phase. Higher urinary bis(monoacylglycerol)phosphate (BMP) levels associate with LRRK2 (leucine-rich repeat kinase 2) and GBA1 (glucocerebrosidase) mutations, and are considered as potential noninvasive biomarkers for predicting those mutations and PD progression. [...] Read more.

Parkinson’s disease (PD) is a common neurodegenerative disorder with a prolonged prodromal phase. Higher urinary bis(monoacylglycerol)phosphate (BMP) levels associate with LRRK2 (leucine-rich repeat kinase 2) and GBA1 (glucocerebrosidase) mutations, and are considered as potential noninvasive biomarkers for predicting those mutations and PD progression. However, their reliability has been questioned, with inadequately investigated genetics, cohorts, and population. In this study, multiple statistical hypothesis tests were employed on urinary BMP levels and sequences of 90 PD-risk single nucleotide polymorphisms (SNPs) from Parkinson’s Progression Markers Institution (PPMI) participants. Those SNPs were categorized into four groups based on their impact on BMP levels in various cohorts. Variants rs34637584 ^G/A and rs34637584 ^A/A (LRRK2 G2019S) were identified as the most relevant on increasing urinary BMP levels in the PD cohort. Meanwhile, rs76763715 ^T/T (GBA1) was the primary factor elevating BMP levels in the prodromal cohort compared to its T/C and C/C variants (N370S) and the PD cohort. Proteomics analysis indicated the changed transport pathways may be the reasons for elevated BMP levels in prodromal patients. Our findings demonstrated that higher urinary BMP levels alone were not reliable biomarkers for PD progression or gene mutations but might serve as supplementary indicators for early diagnosis and treatment. Full article

(This article belongs to the Special Issue Understanding Parkinson's Disease)

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15 pages, 9928 KiB

Open AccessArticle

Acetylated α-Tubulin and α-Synuclein: Physiological Interplay and Contribution to α-Synuclein Oligomerization

by Alessandra Maria Calogero, Milo Jarno Basellini, Huseyin Berkcan Isilgan, Francesca Longhena, Arianna Bellucci, Samanta Mazzetti, Chiara Rolando, Gianni Pezzoli and Graziella Cappelletti

Int. J. Mol. Sci. 2023, 24(15), 12287; https://doi.org/10.3390/ijms241512287 - 31 Jul 2023

Cited by 4 | Viewed by 1854

Abstract

Emerging evidence supports that altered α-tubulin acetylation occurs in Parkinson’s disease (PD), a neurodegenerative disorder characterized by the deposition of α-synuclein fibrillary aggregates within Lewy bodies and nigrostriatal neuron degeneration. Nevertheless, studies addressing the interplay between α-tubulin acetylation and α-synuclein are lacking. Here, [...] Read more.

Emerging evidence supports that altered α-tubulin acetylation occurs in Parkinson’s disease (PD), a neurodegenerative disorder characterized by the deposition of α-synuclein fibrillary aggregates within Lewy bodies and nigrostriatal neuron degeneration. Nevertheless, studies addressing the interplay between α-tubulin acetylation and α-synuclein are lacking. Here, we investigated the relationship between α-synuclein and microtubules in primary midbrain murine neurons and the substantia nigra of post-mortem human brains. Taking advantage of immunofluorescence and Proximity Ligation Assay (PLA), a method allowing us to visualize protein–protein interactions in situ, combined with confocal and super-resolution microscopy, we found that α-synuclein and acetylated α-tubulin colocalized and were in close proximity. Next, we employed an α-synuclein overexpressing cellular model and tested the role of α-tubulin acetylation in α-synuclein oligomer formation. We used the α-tubulin deacetylase HDAC6 inhibitor Tubacin to modulate α-tubulin acetylation, and we evaluated the presence of α-synuclein oligomers by PLA. We found that the increase in acetylated α-tubulin significantly induced α-synuclein oligomerization. In conclusion, we unraveled the link between acetylated α-tubulin and α-synuclein and demonstrated that α-tubulin acetylation could trigger the early step of α-synuclein aggregation. These data suggest that the proper regulation of α-tubulin acetylation might be considered a therapeutic strategy to take on PD. Full article

(This article belongs to the Special Issue Understanding Parkinson's Disease)

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26 pages, 9381 KiB

Open AccessArticle

Rotenone Blocks the Glucocerebrosidase Enzyme and Induces the Accumulation of Lysosomes and Autophagolysosomes Independently of LRRK2 Kinase in HEK-293 Cells

by Laura Patricia Perez-Abshana, Miguel Mendivil-Perez, Carlos Velez-Pardo and Marlene Jimenez-Del-Rio

Int. J. Mol. Sci. 2023, 24(13), 10589; https://doi.org/10.3390/ijms241310589 - 24 Jun 2023

Cited by 5 | Viewed by 2197

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra and the intraneuronal presence of Lewy bodies (LBs), composed of aggregates of phosphorylated alpha-synuclein at residue Ser¹²⁹ (p-Ser¹²⁹α-Syn). Unfortunately, no [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra and the intraneuronal presence of Lewy bodies (LBs), composed of aggregates of phosphorylated alpha-synuclein at residue Ser¹²⁹ (p-Ser¹²⁹α-Syn). Unfortunately, no curative treatment is available yet. To aggravate matters further, the etiopathogenesis of the disorder is still unresolved. However, the neurotoxin rotenone (ROT) has been implicated in PD. Therefore, it has been widely used to understand the molecular mechanism of neuronal cell death. In the present investigation, we show that ROT induces two convergent pathways in HEK-293 cells. First, ROT generates H₂O₂, which, in turn, either oxidizes the stress sensor protein DJ-Cys¹⁰⁶-SH into DJ-1Cys¹⁰⁶SO₃ or induces the phosphorylation of the protein LRRK2 kinase at residue Ser³⁹⁵ (p-Ser³⁹⁵ LRRK2). Once active, the kinase phosphorylates α-Syn (at Ser¹²⁹), induces the loss of mitochondrial membrane potential (ΔΨ_m), and triggers the production of cleaved caspase 3 (CC3), resulting in signs of apoptotic cell death. ROT also reduces glucocerebrosidase (GCase) activity concomitant with the accumulation of lysosomes and autophagolysosomes reflected by the increase in LC3-II (microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate II) markers in HEK-293 cells. Second, the exposure of HEK-293 LRRK2 knockout (KO) cells to ROT displays an almost-normal phenotype. Indeed, KO cells showed neither H₂O₂, DJ-1Cys¹⁰⁶SO_3, p-Ser³⁹⁵ LRRK2, p-Ser¹²⁹α-Syn, nor CC3 but displayed high ΔΨ_m, reduced GCase activity, and the accumulation of lysosomes and autophagolysosomes. Similar observations are obtained when HEK-293 LRRK2 wild-type (WT) cells are exposed to the inhibitor GCase conduritol-β-epoxide (CBE). Taken together, these observations imply that the combined development of LRRK2 inhibitors and compounds for recovering GCase activity might be promising therapeutic agents for PD. Full article

(This article belongs to the Special Issue Understanding Parkinson's Disease)

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23 pages, 10958 KiB

Open AccessArticle

LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis

by Diana Alejandra Quintero-Espinosa, Sabina Sanchez-Hernandez, Carlos Velez-Pardo, Francisco Martin and Marlene Jimenez-Del-Rio

Int. J. Mol. Sci. 2023, 24(13), 10474; https://doi.org/10.3390/ijms241310474 - 22 Jun 2023

Cited by 10 | Viewed by 2988

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been linked to dopaminergic neuronal vulnerability to oxidative stress (OS), mitochondrial impairment, and increased cell death in idiopathic and familial Parkinson’s disease (PD). However, how exactly this kinase participates in the OS-mitochondria-apoptosis connection is still unknown. We [...] Read more.

Leucine-rich repeat kinase 2 (LRRK2) has been linked to dopaminergic neuronal vulnerability to oxidative stress (OS), mitochondrial impairment, and increased cell death in idiopathic and familial Parkinson’s disease (PD). However, how exactly this kinase participates in the OS-mitochondria-apoptosis connection is still unknown. We used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 LRRK2 knockout (KO) in the human embryonic kidney cell line 293 (HEK-293) to evaluate the cellular response to the mitochondrial inhibitor complex I rotenone (ROT), a well-known OS and cell death inducer. We report successful knockout of the LRRK2 gene in HEK-293 cells using CRISPR editing (ICE, approximately 60%) and flow cytometry (81%) analyses. We found that HEK-293 LRRK2 WT cells exposed to rotenone (ROT, 50 μM) resulted in a significant increase in intracellular reactive oxygen species (ROS, +7400%); oxidized DJ-1-Cys¹⁰⁶-SO₃ (+52%); phosphorylation of LRRK2 (+70%) and c-JUN (+171%); enhanced expression of tumor protein (TP53, +2000%), p53 upregulated modulator of apoptosis (PUMA, +1950%), and Parkin (PRKN, +22%); activation of caspase 3 (CASP3, +8000%), DNA fragmentation (+35%) and decreased mitochondrial membrane potential (ΔΨm, −58%) and PTEN induced putative kinase 1 (PINK1, −49%) when compared to untreated cells. The translocation of the cytoplasmic fission protein dynamin-related Protein 1 (DRP1) to mitochondria was also observed by colocalization with translocase of the outer membrane 20 (TOM20). Outstandingly, HEK-293 LRRK2 KO cells treated with ROT showed unaltered OS and apoptosis markers. We conclude that loss of LRRK2 causes HEK-293 to be resistant to ROT-induced OS, mitochondrial damage, and apoptosis in vitro. Our data support the hypothesis that LRRK2 acts as a proapoptotic kinase by regulating mitochondrial proteins (e.g., PRKN, PINK1, DRP1, and PUMA), transcription factors (e.g., c-JUN and TP53), and CASP3 in cells under stress conditions. Taken together, these observations suggest that LRRK2 is an important kinase in the pathogenesis of PD. Full article

(This article belongs to the Special Issue Understanding Parkinson's Disease)

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13 pages, 1983 KiB

Open AccessArticle

Effect of 12-Week BMI-Based Vitamin D₃ Supplementation in Parkinson’s Disease with Deep Brain Stimulation on Physical Performance, Inflammation, and Vitamin D Metabolites

by Zofia Kinga Bytowska, Daria Korewo-Labelle, Paweł Berezka, Konrad Kowalski, Katarzyna Przewłócka, Witold Libionka, Wojciech Kloc and Jan Jacek Kaczor

Int. J. Mol. Sci. 2023, 24(12), 10200; https://doi.org/10.3390/ijms241210200 - 15 Jun 2023

Cited by 6 | Viewed by 2327

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease. To manage motor symptoms not controlled adequately with medication, deep brain stimulation (DBS) is used. PD patients often manifest vitamin D deficiency, which may be connected with a higher risk of falls. We [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative disease. To manage motor symptoms not controlled adequately with medication, deep brain stimulation (DBS) is used. PD patients often manifest vitamin D deficiency, which may be connected with a higher risk of falls. We administered a 12-week vitamin D₃ supplementation based on BMI (with higher doses given to patients with higher BMI) to investigate its effects on physical performance and inflammation status in PD patients with DBS. Patients were randomly divided into two groups: treated with vitamin D₃ (VitD, n = 13), and supplemented with vegetable oil as the placebo group (PL, n = 16). Patients underwent functional tests to assess their physical performance three times during this study. The serum 25(OH)D₃ concentration increased to the recommended level of 30 ng/mL in the VitD group, and a significant elevation in vitamin D metabolites in this group was found. We observed significant improvement in the Up and Go and the 6 MWT in the VitD group. In inflammation status, we noticed a trend toward a decrease in the VitD group. To conclude, achieving the optimal serum 25(OH)D₃ concentration is associated with better functional test performance and consequently may have a positive impact on reducing falling risk in PD. Full article

(This article belongs to the Special Issue Understanding Parkinson's Disease)

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Review

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15 pages, 1349 KiB

Open AccessReview

Clinical and Non-Clinical Cardiovascular Disease Associated Pathologies in Parkinson’s Disease

by Bonn Lee, Charlotte Edling, Shiraz Ahmad, Fiona E. N. LeBeau, Gary Tse and Kamalan Jeevaratnam

Int. J. Mol. Sci. 2023, 24(16), 12601; https://doi.org/10.3390/ijms241612601 - 9 Aug 2023

Cited by 2 | Viewed by 1593

Abstract

Despite considerable breakthroughs in Parkinson’s disease (PD) research, understanding of non-motor symptoms (NMS) in PD remains limited. The lack of basic level models that can properly recapitulate PD NMS either in vivo or in vitro complicates matters. Even so, recent research advances have [...] Read more.

Despite considerable breakthroughs in Parkinson’s disease (PD) research, understanding of non-motor symptoms (NMS) in PD remains limited. The lack of basic level models that can properly recapitulate PD NMS either in vivo or in vitro complicates matters. Even so, recent research advances have identified cardiovascular NMS as being underestimated in PD. Considering that a cardiovascular phenotype reflects sympathetic autonomic dysregulation, cardiovascular symptoms of PD can play a pivotal role in understanding the pathogenesis of PD. In this study, we have reviewed clinical and non-clinical published papers with four key parameters: cardiovascular disease risks, electrocardiograms (ECG), neurocardiac lesions in PD, and fundamental electrophysiological studies that can be linked to the heart. We have highlighted the points and limitations that the reviewed articles have in common. ECG and pathological reports suggested that PD patients may undergo alterations in neurocardiac regulation. The pathological evidence also suggested that the hearts of PD patients were involved in alpha-synucleinopathy. Finally, there is to date little research available that addresses the electrophysiology of in vitro Parkinson’s disease models. For future reference, research that can integrate cardiac electrophysiology and pathological alterations is required. Full article

(This article belongs to the Special Issue Understanding Parkinson's Disease)

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17 pages, 1012 KiB

Open AccessReview

Physiological and Pathological Functions of Neuronal Hemoglobin: A Key Underappreciated Protein in Parkinson’s Disease

by Ran Zheng, Yiqun Yan, Jiali Pu and Baorong Zhang

Int. J. Mol. Sci. 2022, 23(16), 9088; https://doi.org/10.3390/ijms23169088 - 13 Aug 2022

Cited by 6 | Viewed by 3475

Abstract

The expression of Hemoglobin (Hb) is not restricted to erythrocytes but is also present in neurons. Hb is selectively enriched in vulnerable mesencephalic dopaminergic neurons of Parkinson’s disease (PD) instead of resistant neurons. Controversial results of neuronal Hb levels have been reported in [...] Read more.

The expression of Hemoglobin (Hb) is not restricted to erythrocytes but is also present in neurons. Hb is selectively enriched in vulnerable mesencephalic dopaminergic neurons of Parkinson’s disease (PD) instead of resistant neurons. Controversial results of neuronal Hb levels have been reported in postmortem brains of PD patients: although neuronal Hb levels may decline in PD patients, elderly men with higher Hb levels have an increased risk of developing PD. α-synuclein, a key protein involved in PD pathology, interacts directly with Hb protein and forms complexes in erythrocytes and brains of monkeys and humans. These complexes increase in erythrocytes and striatal cytoplasm, while they decrease in striatal mitochondria with aging. Besides, the colocalization of serine 129-phosphorylated (Pser129) α-synuclein and Hb β chains have been found in the brains of PD patients. Several underlying molecular mechanisms involving mitochondrial homeostasis, α-synuclein accumulation, iron metabolism, and hormone-regulated signaling pathways have been investigated to assess the relationship between neuronal Hb and PD development. The formation of fibrils with neuronal Hb in various neurodegenerative diseases may indicate a common fibrillization pathway and a widespread target that could be applied in neurodegeneration therapy. Full article

(This article belongs to the Special Issue Understanding Parkinson's Disease)

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8 pages, 4988 KiB

Open AccessCase Report

Metabolic Brain Changes Can Predict the Underlying Pathology in Neurodegenerative Brain Disorders: A Case Report of Sporadic Creutzfeldt–Jakob Disease with Concomitant Parkinson’s Disease

by Tomaž Rus, Jernej Mlakar, Jan Jamšek and Maja Trošt

Int. J. Mol. Sci. 2023, 24(17), 13081; https://doi.org/10.3390/ijms241713081 - 23 Aug 2023

Cited by 1 | Viewed by 1374

Abstract

The co-occurrence of multiple proteinopathies is being increasingly recognized in neurodegenerative disorders and poses a challenge in differential diagnosis and patient selection for clinical trials. Changes in brain metabolism captured by positron emission tomography (PET) with ¹⁸ F-fluorodeoxyglucose (FDG) allow us to differentiate [...] Read more.

The co-occurrence of multiple proteinopathies is being increasingly recognized in neurodegenerative disorders and poses a challenge in differential diagnosis and patient selection for clinical trials. Changes in brain metabolism captured by positron emission tomography (PET) with ¹⁸ F-fluorodeoxyglucose (FDG) allow us to differentiate between different neurodegenerative disorders either by visual exploration or by studying disease-specific metabolic networks in individual patients. However, the impact of multiple proteinopathies on brain metabolism and metabolic networks remains unknown due to the absence of pathological studies. In this case study, we present a 67-year-old patient with rapidly progressing dementia clinically diagnosed with probable sporadic Creutzfeldt–Jakob disease (sCJD). However, in addition to the expected pronounced cortical and subcortical hypometabolism characteristic of sCJD, the brain FDG PET revealed an intriguing finding of unexpected relative hypermetabolism in the bilateral putamina, raising suspicions of coexisting Parkinson’s disease (PD). Additional investigation of disease-specific metabolic brain networks revealed elevated expression of both CJD-related pattern (CJDRP) and PD-related pattern (PDRP) networks. The patient eventually developed akinetic mutism and passed away seven weeks after symptom onset. Neuropathological examination confirmed neuropathological changes consistent with sCJD and the presence of Lewy bodies confirming PD pathology. Additionally, hyperphosphorylated tau and TDP-43 pathology were observed, a combination of four proteinopathies that had not been previously reported. Overall, this case provides valuable insights into the complex interplay of neurodegenerative pathologies and their impact on metabolic brain changes, emphasizing the role of metabolic brain imaging in evaluating potential presence of multiple proteinopathies. Full article

(This article belongs to the Special Issue Understanding Parkinson's Disease)

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