International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Neurobiology of Parkinson’s Disease

by Micaela Morelli and Annalisa Pinna

Int. J. Mol. Sci. 2023, 24(12), 9933; https://doi.org/10.3390/ijms24129933 - 09 Jun 2023

Cited by 1 | Viewed by 1213

Abstract

Parkinson’s disease (PD) is one of the most rapidly growing neurological disorders [...] Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

Research

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8 pages, 790 KiB

Open AccessCommunication

Oligomeric Alpha-Synuclein and STX-1A from Neural-Derived Extracellular Vesicles (NDEVs) as Possible Biomarkers of REM Sleep Behavior Disorder in Parkinson’s Disease: A Preliminary Cohort Study

by Mario Meloni, Cristina Agliardi, Franca Rosa Guerini, Francesca Lea Saibene, Anna Vera Milner, Milena Zanzottera, Elisabetta Bolognesi, Monica Puligheddu, Michela Figorilli, Jorge Navarro and Mario Clerici

Int. J. Mol. Sci. 2023, 24(10), 8839; https://doi.org/10.3390/ijms24108839 - 16 May 2023

Cited by 3 | Viewed by 1264

Abstract

REM sleep behavior disorder (RBD) has a tighter link with synucleinopathies than other neurodegenerative disorders. Parkinson’s Disease (PD) patients with RBD have a more severe motor and cognitive impairment; biomarkers for RBD are currently unavailable. Synaptic accumulation of α-Syn oligomers and their interaction [...] Read more.

REM sleep behavior disorder (RBD) has a tighter link with synucleinopathies than other neurodegenerative disorders. Parkinson’s Disease (PD) patients with RBD have a more severe motor and cognitive impairment; biomarkers for RBD are currently unavailable. Synaptic accumulation of α-Syn oligomers and their interaction with SNARE proteins is responsible for synaptic dysfunction in PD. We verified whether oligomeric α-Syn and SNARE components in neural-derived extracellular vesicles (NDEVs) in serum could be biomarkers for RBD. Forty-seven PD patients were enrolled, and the RBD Screening Questionnaire (RBDSQ) was compiled. A cut-off score > 6 to define probable RBD (p-RBD) and probable non-RBD (p non-RBD) was used. NDEVs were isolated from serum by immunocapture, and oligomeric α-Syn and SNARE complex components VAMP-2 and STX-1 were measured by ELISA. NDEVs’ STX-1A resulted in being decreased in p-RBD compared to p non-RBD PD patients. A positive correlation between NDEVs’ oligomeric α-Syn and RBDSQ total score was found (p = 0.032). Regression analysis confirmed a significant association between NDEVs’ oligomeric α-Syn concentration and RBD symptoms (p = 0.033) independent from age, disease duration, and motor impairment severity. Our findings suggest that synuclein-mediated neurodegeneration in PD-RBD is more diffuse. NDEVs’ oligomeric α-Syn and SNARE complex components’ serum concentrations could be regarded as reliable biomarkers for the RBD-specific PD endophenotype. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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22 pages, 4837 KiB

Open AccessArticle

Treadmill Exercise Alleviates Cognition Disorder by Activating the FNDC5: Dual Role of Integrin αV/β5 in Parkinson’s Disease

by Chuanxi Tang, Mengting Liu, Zihang Zhou, Hao Li, Chenglin Yang, Li Yang and Jie Xiang

Int. J. Mol. Sci. 2023, 24(9), 7830; https://doi.org/10.3390/ijms24097830 - 25 Apr 2023

Cited by 3 | Viewed by 2078

Abstract

Parkinson’s disease with cognitive impairment (PD-CI) results in several clinical outcomes for which specific treatment is lacking. Although the pathogenesis of PD-CI has not yet been fully elucidated, it is related to neuronal plasticity decline in the hippocampus region. The dopaminergic projections from [...] Read more.

Parkinson’s disease with cognitive impairment (PD-CI) results in several clinical outcomes for which specific treatment is lacking. Although the pathogenesis of PD-CI has not yet been fully elucidated, it is related to neuronal plasticity decline in the hippocampus region. The dopaminergic projections from the substantia nigra to the hippocampus are critical in regulating hippocampal plasticity. Recently, aerobic exercise has been recognized as an effective therapeutic strategy for enhancing plasticity through the secretion of various muscle factors. The exact role of FNDC5—an upregulated, newly identified myokine produced after exercise—in mediating hippocampal plasticity and regional dopaminergic projections in PD-CI remains unclear. In this study, the effect of treadmill exercise on hippocampal synaptic plasticity was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced chronic PD models. The results showed that treadmill exercise substantially alleviated the motor dysfunction, cognition disorder, and dopaminergic neuron degeneration induced by MPTP. Here, we discovered that the quadriceps, serum, and brain FNDC5 levels were lower in PD mice and that intervention with treadmill exercise restored FNDC5 levels. Moreover, treadmill exercise enhanced the synaptic plasticity of hippocampal pyramidal neurons via increased dopamine levels and BDNF in the PD mice. The direct protective effect of FNDC5 is achieved by promoting the secretion of BDNF in the hippocampal neurons via binding the integrin αVβ5 receptor, thereby improving synaptic plasticity. Regarding the indirect protection effect, FNDC5 promotes the dopaminergic connection from the substantia nigra to the hippocampus by mediating the interaction between the integrin αVβ5 of the hippocampal neurons and the CD90 molecules on the membrane of dopaminergic terminals. Our findings demonstrated that treadmill exercise could effectively alleviate cognitive disorders via the activation of the FNDC5–BDNF pathway and enhance the dopaminergic synaptic connection from SNpc to the hippocampus in the MPTP-induced chronic PD model. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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16 pages, 3392 KiB

Open AccessArticle

Characterization of Lipopolysaccharide Effects on LRRK2 Signaling in RAW Macrophages

by Asmaa Oun, Emmy Hoeksema, Ahmed Soliman, Famke Brouwer, Fabiola García-Reyes, Henderikus Pots, Marina Trombetta-Lima, Arjan Kortholt and Amalia M. Dolga

Int. J. Mol. Sci. 2023, 24(2), 1644; https://doi.org/10.3390/ijms24021644 - 13 Jan 2023

Cited by 3 | Viewed by 2060

Abstract

Dysfunction of the immune system and mitochondrial metabolism has been associated with Parkinson’s disease (PD) pathology. Mutations and increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) are linked to both idiopathic and familial PD. However, the function of LRRK2 in the immune [...] Read more.

Dysfunction of the immune system and mitochondrial metabolism has been associated with Parkinson’s disease (PD) pathology. Mutations and increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) are linked to both idiopathic and familial PD. However, the function of LRRK2 in the immune cells under inflammatory conditions is contradictory. Our results showed that lipopolysaccharide (LPS) stimulation increased the kinase activity of LRRK2 in parental RAW 264.7 (WT) cells. In addition to this, LRRK2 deletion in LRRK2 KO RAW 264.7 (KO) cells altered cell morphology following LPS stimulation compared to the WT cells, as shown by an increase in the cell impedance as observed by the xCELLigence measurements. LPS stimulation caused an increase in the cellular reactive oxygen species (ROS) levels in both WT and KO cells. However, WT cells displayed a higher ROS level compared to the KO cells. Moreover, LRRK2 deletion led to a reduction in interleukin-6 (IL-6) inflammatory cytokine and cyclooxygenase-2 (COX-2) expression and an increase in lactate production after LPS stimulation compared to the WT cells. These data illustrate that LRRK2 has an effect on inflammatory processes in RAW macrophages upon LPS stimulation. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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20 pages, 2322 KiB

Open AccessArticle

Whole-Head Functional Near-Infrared Spectroscopy as an Ecological Monitoring Tool for Assessing Cortical Activity in Parkinson’s Disease Patients at Different Stages

by Augusto Bonilauri, Francesca Sangiuliano Intra, Federica Rossetto, Francesca Borgnis, Giuseppe Baselli and Francesca Baglio

Int. J. Mol. Sci. 2022, 23(23), 14897; https://doi.org/10.3390/ijms232314897 - 28 Nov 2022

Cited by 3 | Viewed by 1669

Abstract

Functional near-infrared spectroscopy (fNIRS) is increasingly employed as an ecological neuroimaging technique in assessing age-related chronic neurological disorders, such as Parkinson’s disease (PD), mainly providing a cross-sectional characterization of clinical phenotypes in ecological settings. Current fNIRS studies in PD have investigated the effects [...] Read more.

Functional near-infrared spectroscopy (fNIRS) is increasingly employed as an ecological neuroimaging technique in assessing age-related chronic neurological disorders, such as Parkinson’s disease (PD), mainly providing a cross-sectional characterization of clinical phenotypes in ecological settings. Current fNIRS studies in PD have investigated the effects of motor and non-motor impairment on cortical activity during gait and postural stability tasks, but no study has employed fNIRS as an ecological neuroimaging tool to assess PD at different stages. Therefore, in this work, we sought to investigate the cortical activity of PD patients during a motor grasping task and its relationship with both the staging of the pathology and its clinical variables. This study considered 39 PD patients (age 69.0 ± 7.64, 38 right-handed), subdivided into two groups at different stages by the Hoehn and Yahr (HY) scale: early PD (ePD; N = 13, HY = [1; 1.5]) and moderate PD (mPD; N = 26, HY = [2; 2.5; 3]). We employed a whole-head fNIRS system with 102 measurement channels to monitor brain activity. Group-level activation maps and region of interest (ROI) analysis were computed for ePD, mPD, and ePD vs. mPD contrasts. A ROI-based correlation analysis was also performed with respect to contrasted subject-level fNIRS data, focusing on age, a Cognitive Reserve Index questionnaire (CRIQ), disease duration, the Unified Parkinson’s Disease Rating Scale (UPDRS), and performances in the Stroop Color and Word (SCW) test. We observed group differences in age, disease duration, and the UPDRS, while no significant differences were found for CRIQ or SCW scores. Group-level activation maps revealed that the ePD group presented higher activation in motor and occipital areas than the mPD group, while the inverse trend was found in frontal areas. Significant correlations with CRIQ, disease duration, the UPDRS, and the SCW were mostly found in non-motor areas. The results are in line with current fNIRS and functional and anatomical MRI scientific literature suggesting that non-motor areas—primarily the prefrontal cortex area—provide a compensation mechanism for PD motor impairment. fNIRS may serve as a viable support for the longitudinal assessment of therapeutic and rehabilitation procedures, and define new prodromal, low-cost, and ecological biomarkers of disease progression. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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13 pages, 1976 KiB

Open AccessArticle

Ncx3-Induced Mitochondrial Dysfunction in Midbrain Leads to Neuroinflammation in Striatum of A53t-α-Synuclein Transgenic Old Mice

by Rossana Di Martino, Maria Josè Sisalli, Rossana Sirabella, Salvatore Della Notte, Domenica Borzacchiello, Antonio Feliciello, Lucio Annunziato and Antonella Scorziello

Int. J. Mol. Sci. 2021, 22(15), 8177; https://doi.org/10.3390/ijms22158177 - 30 Jul 2021

Cited by 10 | Viewed by 2485

Abstract

The exact mechanism underlying selective dopaminergic neurodegeneration is not completely understood. The complex interplay among toxic alpha-synuclein aggregates, oxidative stress, altered intracellular Ca²⁺-homeostasis, mitochondrial dysfunction and disruption of mitochondrial integrity is considered among the pathogenic mechanisms leading to dopaminergic neuronal loss. [...] Read more.

The exact mechanism underlying selective dopaminergic neurodegeneration is not completely understood. The complex interplay among toxic alpha-synuclein aggregates, oxidative stress, altered intracellular Ca²⁺-homeostasis, mitochondrial dysfunction and disruption of mitochondrial integrity is considered among the pathogenic mechanisms leading to dopaminergic neuronal loss. We herein investigated the molecular mechanisms leading to mitochondrial dysfunction and its relationship with activation of the neuroinflammatory process occurring in Parkinson’s disease. To address these issues, experiments were performed in vitro and in vivo in mice carrying the human mutation of α-synuclein A53T under the prion murine promoter. In these models, the expression and activity of NCX isoforms, a family of important transporters regulating ionic homeostasis in mammalian cells working in a bidirectional way, were evaluated in neurons and glial cells. Mitochondrial function was monitored with confocal microscopy and fluorescent dyes to measure mitochondrial calcium content and mitochondrial membrane potential. Parallel experiments were performed in 4 and 16-month-old A53T-α-synuclein Tg mice to correlate the functional data obtained in vitro with mitochondrial dysfunction and neuroinflammation through biochemical analysis. The results obtained demonstrated: 1. in A53T mice mitochondrial dysfunction occurs early in midbrain and later in striatum; 2. mitochondrial dysfunction occurring in the midbrain is mediated by the impairment of NCX3 protein expression in neurons and astrocytes; 3. mitochondrial dysfunction occurring early in midbrain triggers neuroinflammation later into the striatum, thus contributing to PD progression during mice aging. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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19 pages, 10054 KiB

Open AccessArticle

Glucocerebrosidase Gene Therapy Induces Alpha-Synuclein Clearance and Neuroprotection of Midbrain Dopaminergic Neurons in Mice and Macaques

by Diego Sucunza, Alberto J. Rico, Elvira Roda, María Collantes, Gloria González-Aseguinolaza, Ana I. Rodríguez-Pérez, Iván Peñuelas, Alfonso Vázquez, José L. Labandeira-García, Vania Broccoli and José L. Lanciego

Int. J. Mol. Sci. 2021, 22(9), 4825; https://doi.org/10.3390/ijms22094825 - 01 May 2021

Cited by 17 | Viewed by 3655

Abstract

Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson’s disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD—even when considering idiopathic forms of PD—has recently paved [...] Read more.

Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson’s disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD—even when considering idiopathic forms of PD—has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease modeling purposes, both in mice as well as in nonhuman primates (NHPs), further inducing a progressive neuronal death in the substantia nigra pars compacta (SNpc). Next, another vector coding for the GBA1 gene (rAAV9-GBA1) was unilaterally delivered in the SNpc of mice and NHPs one month after the initial insult, together with the contralateral delivery of an empty/null rAAV9 for control purposes. Obtained results showed that GCase enhancement reduced alpha-synuclein burden, leading to improved survival of dopaminergic neurons. Data reported here support using GCase gene therapy as a disease-modifying treatment for PD and related synucleinopathies, including idiopathic forms of these disorders. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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19 pages, 5441 KiB

Open AccessArticle

A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity

by Lorena Cuenca-Bermejo, Elisa Pizzichini, Valeria C. Gonçalves, María Guillén-Díaz, Elena Aguilar-Moñino, Consuelo Sánchez-Rodrigo, Ana-María González-Cuello, Emiliano Fernández-Villalba and María Trinidad Herrero

Int. J. Mol. Sci. 2021, 22(9), 4341; https://doi.org/10.3390/ijms22094341 - 21 Apr 2021

Cited by 2 | Viewed by 2102

Abstract

The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer’s disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study [...] Read more.

The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer’s disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study Parkinson’s disease. To test this idea, 10 adult male O. degus were divided into control group and MPTP-intoxicated animals. Motor condition and cognition were examined. Dopaminergic degeneration was studied in the ventral mesencephalon and in the striatum. Neuroinflammation was also evaluated in the ventral mesencephalon, in the striatum and in the dorsal hippocampus. MPTP animals showed significant alterations in motor activity and in visuospatial memory. Postmortem analysis revealed a significant decrease in the number of dopaminergic neurons in the ventral mesencephalon of MPTP animals, although no differences were found in their striatal terminals. We observed a significant increase in neuroinflammatory responses in the mesencephalon, in the striatum and in the hippocampus of MPTP-intoxicated animals. Additionally, changes in the subcellular expression of the calcium-binding protein S100β were found in the astrocytes in the nigrostriatal pathway. These findings prove for the first time that O. degus are sensitive to MPTP intoxication and, therefore, is a suitable model for experimental Parkinsonism in the context of aging. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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11 pages, 1605 KiB

Open AccessArticle

A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

by Jun Ogata, Kentaro Hirao, Kenya Nishioka, Arisa Hayashida, Yuanzhe Li, Hiroyo Yoshino, Soichiro Shimizu, Nobutaka Hattori and Yuzuru Imai

Int. J. Mol. Sci. 2021, 22(7), 3708; https://doi.org/10.3390/ijms22073708 - 02 Apr 2021

Cited by 6 | Viewed by 2484

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein [...] Read more.

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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10 pages, 2189 KiB

Open AccessArticle

Therapeutic Potential of Magnetic Nanoparticle-Based Human Adipose-Derived Stem Cells in a Mouse Model of Parkinson’s Disease

by Ka Young Kim and Keun-A Chang

Int. J. Mol. Sci. 2021, 22(2), 654; https://doi.org/10.3390/ijms22020654 - 11 Jan 2021

Cited by 12 | Viewed by 2519

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Several treatments for PD have focused on the management of physical symptoms using dopaminergic agents. However, these treatments induce various adverse effects, including hallucinations [...] Read more.

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Several treatments for PD have focused on the management of physical symptoms using dopaminergic agents. However, these treatments induce various adverse effects, including hallucinations and cognitive impairment, owing to non-targeted brain delivery, while alleviating motor symptoms. Furthermore, these therapies are not considered ultimate cures owing to limited brain self-repair and regeneration abilities. In the present study, we aimed to investigate the therapeutic potential of human adipose-derived stem cells (hASCs) using magnetic nanoparticles in a 6-hydroxydopamine (6-OHDA)-induced PD mouse model. We used the Maestro imaging system and magnetic resonance imaging (MRI) for in vivo tracking after transplantation of magnetic nanoparticle-loaded hASCs to the PD mouse model. The Maestro imaging system revealed strong hASCs signals in the brains of PD model mice. In particular, MRI revealed hASCs distribution in the substantia nigra of hASCs-injected PD mice. Behavioral evaluations, including apomorphine-induced rotation and rotarod performance, were significantly recovered in hASCs-injected 6-OHDA induced PD mice when compared with saline-treated counterparts. Herein, we investigated whether hASCs transplantation using magnetic nanoparticles recovered motor functions through targeted brain distribution in a 6-OHDA induced PD mice. These results indicate that magnetic nanoparticle-based hASCs transplantation could be a potential therapeutic strategy in PD. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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Review

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14 pages, 336 KiB

Open AccessReview

Parkinson’s Disease: A Prionopathy?

by Sarah Vascellari and Aldo Manzin

Int. J. Mol. Sci. 2021, 22(15), 8022; https://doi.org/10.3390/ijms22158022 - 27 Jul 2021

Cited by 11 | Viewed by 2399

Abstract

The principal pathogenic event in Parkinson’s disease is characterized by the conformational change of α-synuclein, which form pathological aggregates of misfolded proteins, and then accumulate in intraneuronal inclusions causing dopaminergic neuronal loss in specific brain regions. Over the last few years, a revolutionary [...] Read more.

The principal pathogenic event in Parkinson’s disease is characterized by the conformational change of α-synuclein, which form pathological aggregates of misfolded proteins, and then accumulate in intraneuronal inclusions causing dopaminergic neuronal loss in specific brain regions. Over the last few years, a revolutionary theory has correlated Parkinson’s disease and other neurological disorders with a shared mechanism, which determines α-synuclein aggregates and progresses in the host in a prion-like manner. In this review, the main characteristics shared between α-synuclein and prion protein are compared and the cofactors that influence the remodeling of native protein structures and pathogenetic mechanisms underlying neurodegeneration are discussed. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

20 pages, 1087 KiB

Open AccessReview

Adeno-Associated Viral Vectors as Versatile Tools for Parkinson’s Research, Both for Disease Modeling Purposes and for Therapeutic Uses

by Ana Fajardo-Serrano, Alberto J. Rico, Elvira Roda, Adriana Honrubia, Sandra Arrieta, Goiaz Ariznabarreta, Julia Chocarro, Elena Lorenzo-Ramos, Alvaro Pejenaute, Alfonso Vázquez and José Luis Lanciego

Int. J. Mol. Sci. 2021, 22(12), 6389; https://doi.org/10.3390/ijms22126389 - 15 Jun 2021

Cited by 12 | Viewed by 4372

Abstract

It is without any doubt that precision medicine therapeutic strategies targeting neurodegenerative disorders are currently witnessing the spectacular rise of newly designed approaches based on the use of viral vectors as Trojan horses for the controlled release of a given genetic payload. Among [...] Read more.

It is without any doubt that precision medicine therapeutic strategies targeting neurodegenerative disorders are currently witnessing the spectacular rise of newly designed approaches based on the use of viral vectors as Trojan horses for the controlled release of a given genetic payload. Among the different types of viral vectors, adeno-associated viruses (AAVs) rank as the ones most commonly used for the purposes of either disease modeling or for therapeutic strategies. Here, we reviewed the current literature dealing with the use of AAVs within the field of Parkinson’s disease with the aim to provide neuroscientists with the advice and background required when facing a choice on which AAV might be best suited for addressing a given experimental challenge. Accordingly, here we will be summarizing some insights on different AAV serotypes, and which would be the most appropriate AAV delivery route. Next, the use of AAVs for modeling synucleinopathies is highlighted, providing potential readers with a landscape view of ongoing pre-clinical and clinical initiatives pushing forward AAV-based therapeutic approaches for Parkinson’s disease and related synucleinopathies. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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14 pages, 502 KiB

Open AccessReview

Proteolytic α-Synuclein Cleavage in Health and Disease

by Alexandra Bluhm, Sarah Schrempel, Stephan von Hörsten, Anja Schulze and Steffen Roßner

Int. J. Mol. Sci. 2021, 22(11), 5450; https://doi.org/10.3390/ijms22115450 - 21 May 2021

Cited by 14 | Viewed by 3173

Abstract

In Parkinson’s disease, aggregates of α-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary α-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational [...] Read more.

In Parkinson’s disease, aggregates of α-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary α-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational modifications such as phosphorylation, ubiquitination, nitration, glycation, and SUMOylation affect α-synuclein conformation along with its aggregation propensity and neurotoxic profiles. In addition, proteolytic cleavage of α-synuclein by specific proteases results in the formation of a broad spectrum of fragments with consecutively altered and not fully understood physiological and/or pathological properties. In the present review, we summarize the current knowledge on proteolytical α-synuclein cleavage by neurosin, calpain-1, cathepsin D, and matrix metalloproteinase-3 in health and disease. We also shed light on the contribution of the same enzymes to proteolytical processing of pathogenic proteins in Alzheimer’s disease and report potential cross-disease mechanisms of pathogenic protein aggregation. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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13 pages, 2215 KiB

Open AccessReview

Involvement of the Protein Ras Homolog Enriched in the Striatum, Rhes, in Dopaminergic Neurons’ Degeneration: Link to Parkinson’s Disease

by Marcello Serra, Annalisa Pinna, Giulia Costa, Alessandro Usiello, Massimo Pasqualetti, Luigi Avallone, Micaela Morelli and Francesco Napolitano

Int. J. Mol. Sci. 2021, 22(10), 5326; https://doi.org/10.3390/ijms22105326 - 18 May 2021

Cited by 6 | Viewed by 3694

Abstract

Rhes is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. Rhes mRNA is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression [...] Read more.

Rhes is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. Rhes mRNA is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D₂ and adenosine A_2A receptors. Rhes transcript is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, data showed that lack of Rhes enhanced cocaine- and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson’s disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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26 pages, 2246 KiB

Open AccessReview

Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage

by Rafael Franco, Rafael Rivas-Santisteban, Gemma Navarro, Annalisa Pinna and Irene Reyes-Resina

Int. J. Mol. Sci. 2021, 22(9), 4643; https://doi.org/10.3390/ijms22094643 - 28 Apr 2021

Cited by 11 | Viewed by 4111

Abstract

The mechanism of nigral dopaminergic neuronal degeneration in Parkinson’s disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a [...] Read more.

The mechanism of nigral dopaminergic neuronal degeneration in Parkinson’s disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson’s disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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19 pages, 926 KiB

Open AccessReview

Molecular and Genetic Factors Involved in Olfactory and Gustatory Deficits and Associations with Microbiota in Parkinson’s Disease

by Melania Melis, Antje Haehner, Mariano Mastinu, Thomas Hummel and Iole Tomassini Barbarossa

Int. J. Mol. Sci. 2021, 22(8), 4286; https://doi.org/10.3390/ijms22084286 - 20 Apr 2021

Cited by 15 | Viewed by 3749

Abstract

Deficits in olfaction and taste are among the most frequent non-motor manifestations in Parkinson’s disease (PD) that start very early and frequently precede the PD motor symptoms. The limited data available suggest that the basis of the olfactory and gustatory dysfunction related to [...] Read more.

Deficits in olfaction and taste are among the most frequent non-motor manifestations in Parkinson’s disease (PD) that start very early and frequently precede the PD motor symptoms. The limited data available suggest that the basis of the olfactory and gustatory dysfunction related to PD are likely multifactorial and may include the same determinants responsible for other non-motor symptoms of PD. This review describes the most relevant molecular and genetic factors involved in the PD-related smell and taste impairments, and their associations with the microbiota, which also may represent risk factors associated with the disease. Full article

(This article belongs to the Special Issue Neurobiology of Parkinson’s Disease)

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