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17 pages, 2841 KiB

Open AccessArticle

Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease

by Stefano Doccini, Maria Marchese, Federica Morani, Nicola Gammaldi, Serena Mero, Francesco Pezzini, Rabah Soliymani, Melissa Santi, Giovanni Signore, Asahi Ogi, Silvia Rocchiccioli, Katja M. Kanninen, Alessandro Simonati, Maciej M. Lalowski and Filippo M. Santorelli

Cells 2022, 11(11), 1840; https://doi.org/10.3390/cells11111840 - 4 Jun 2022

Cited by 9 | Viewed by 3792

Abstract

CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities [...] Read more.

CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5^−/− mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments. Full article

(This article belongs to the Special Issue Neurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies)

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25 pages, 3365 KiB

Open AccessFeature PaperArticle

Modelling α-Synuclein Aggregation and Neurodegeneration with Fibril Seeds in Primary Cultures of Mouse Dopaminergic Neurons

by Aurore Tourville, David Akbar, Olga Corti, Jochen H. M. Prehn, Ronald Melki, Stéphane Hunot and Patrick P. Michel

Cells 2022, 11(10), 1640; https://doi.org/10.3390/cells11101640 - 13 May 2022

Cited by 8 | Viewed by 4381

Abstract

To model α-Synuclein (αS) aggregation and neurodegeneration in Parkinson’s disease (PD), we established cultures of mouse midbrain dopamine (DA) neurons and chronically exposed them to fibrils 91 (F91) generated from recombinant human αS. We found that F91 have an exquisite propensity to seed [...] Read more.

To model α-Synuclein (αS) aggregation and neurodegeneration in Parkinson’s disease (PD), we established cultures of mouse midbrain dopamine (DA) neurons and chronically exposed them to fibrils 91 (F91) generated from recombinant human αS. We found that F91 have an exquisite propensity to seed the aggregation of endogenous αS in DA neurons when compared to other neurons in midbrain cultures. Until two weeks post-exposure, somal aggregation in DA neurons increased with F91 concentrations (0.01–0.75 μM) and the time elapsed since the initiation of seeding, with, however, no evidence of DA cell loss within this time interval. Neither toxin-induced mitochondrial deficits nor genetically induced loss of mitochondrial quality control mechanisms promoted F91-mediated αS aggregation or neurodegeneration under these conditions. Yet, a significant loss of DA neurons (~30%) was detectable three weeks after exposure to F91 (0.5 μM), i.e., at a time point where somal aggregation reached a plateau. This loss was preceded by early deficits in DA uptake. Unlike αS aggregation, the loss of DA neurons was prevented by treatment with GDNF, suggesting that αS aggregation in DA neurons may induce a form of cell death mimicking a state of trophic factor deprivation. Overall, our model system may be useful for exploring PD-related pathomechanisms and for testing molecules of therapeutic interest for this disorder. Full article

(This article belongs to the Special Issue Neurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies)

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27 pages, 6778 KiB

Open AccessArticle

Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS

by René Günther, Arun Pal, Chloe Williams, Vitaly L. Zimyanin, Maria Liehr, Cläre von Neubeck, Mechthild Krause, Mrudula G. Parab, Susanne Petri, Norman Kalmbach, Stefan L. Marklund, Jared Sterneckert, Peter Munch Andersen, Florian Wegner, Jonathan D. Gilthorpe and Andreas Hermann

Cells 2022, 11(7), 1246; https://doi.org/10.3390/cells11071246 - 6 Apr 2022

Cited by 17 | Viewed by 5106

Abstract

Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to [...] Read more.

Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90A^hom, R115G^het or A4V^het) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90A^hom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115G^het and A4V^het mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS. Full article

(This article belongs to the Special Issue Neurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies)

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15 pages, 3895 KiB

Open AccessArticle

LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss

by Dong-Hwan Ho, Daleum Nam, Mikyoung Seo, Sung-Woo Park, Wongi Seol and Ilhong Son

Cells 2022, 11(5), 861; https://doi.org/10.3390/cells11050861 - 2 Mar 2022

Cited by 15 | Viewed by 3372

Abstract

Evidence suggests that crosstalk occurs between microglial leucine-rich repeat kinase 2 (LRRK2)—a regulator of neuroinflammation—and neuron-released α-synuclein (αSyn)—a promoter of microglial activation and neuroinflammatory responses—in neuroinflammation-mediated Parkinson’s disease (PD) progression. Therefore, we examined whether LRRK2 inhibition reduces the responses of microglia to neuroinflammation [...] Read more.

Evidence suggests that crosstalk occurs between microglial leucine-rich repeat kinase 2 (LRRK2)—a regulator of neuroinflammation—and neuron-released α-synuclein (αSyn)—a promoter of microglial activation and neuroinflammatory responses—in neuroinflammation-mediated Parkinson’s disease (PD) progression. Therefore, we examined whether LRRK2 inhibition reduces the responses of microglia to neuroinflammation caused by neuron-released αSyn. We examined the neuroinflammatory responses provoked by Toll-like receptor 2 (TLR2)-positive αSyn of neuronal cells using an LRRK2 inhibitor in the mouse glioma cells, rat primary microglia, and human microglia cell line; and the effects of LRRK2 inhibitor in the co-culture of ectopic αSyn-expressing human neuroblastoma cells and human microglia cells and in mouse models by injecting αSyn. We analyzed the association between LRRK2 activity and αSyn oligomer and TLR2 levels in the substantia nigra tissues of human patients with idiopathic PD (iPD). The TLR2-specific αSyn elevated LRRK2 activity and neuroinflammation, and the LRRK2 inhibitor ameliorated neuroinflammatory responses in various microglia cells, alleviated neuronal degeneration along with neuroinflammation in the co-culture, and blocked the further progression of locomotor failure and dopaminergic neuronal degeneration caused by TLR2-specific αSyn in mice. Furthermore, LRRK2 phosphorylation was increased in patients with iPD showing αSyn-specific high TLR2 level. These results suggest the application of LRRK2 inhibitors as a novel therapeutic approach against αSyn-mediated PD progression. Full article

(This article belongs to the Special Issue Neurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies)

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22 pages, 4007 KiB

Open AccessArticle

A Distinct Hibiscus sabdariffa Extract Prevents Iron Neurotoxicity, a Driver of Multiple Sclerosis Pathology

by Manoj Kumar Mishra, Jianxiong Wang, Reza Mirzaei, Rigel Chan, Helvira Melo, Ping Zhang, Chang-Chun Ling, Aldo Bruccoleri, Lin Tang and V. Wee Yong

Cells 2022, 11(3), 440; https://doi.org/10.3390/cells11030440 - 27 Jan 2022

Cited by 5 | Viewed by 4875

Abstract

Iron deposition in the brain begins early in multiple sclerosis (MS) and continues unabated. Ferrous iron is toxic to neurons, yet the therapies used in MS do not counter iron neurotoxicity. Extracts of Hibiscus sabdariffa (HS) are used in many cultures for medicinal [...] Read more.

Iron deposition in the brain begins early in multiple sclerosis (MS) and continues unabated. Ferrous iron is toxic to neurons, yet the therapies used in MS do not counter iron neurotoxicity. Extracts of Hibiscus sabdariffa (HS) are used in many cultures for medicinal purposes. We collected a distinct HS extract and found that it abolished the killing of neurons by iron in culture; medications used in MS were ineffective when similarly tested. Neuroprotection by HS was not due to iron chelation or anthocyanin content. In free radical scavenging assays, HS was equipotent to alpha lipoic acid, an anti-oxidant being tested in MS. However, alpha lipoic acid was only modestly protective against iron-mediated killing. Moreover, a subfraction of HS without radical scavenging activity negated iron toxicity, whereas a commercial hibiscus preparation with anti-oxidant activity could not. The idea that HS might have altered properties within neurons to confer neuroprotection is supported by its amelioration of toxicity caused by other toxins: beta-amyloid, rotenone and staurosporine. Finally, in a mouse model of MS, HS reduced disability scores and ameliorated the loss of axons in the spinal cord. HS holds therapeutic potential to counter iron neurotoxicity, an unmet need that drives the progression of disability in MS. Full article

(This article belongs to the Special Issue Neurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies)

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Review

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22 pages, 1161 KiB

Open AccessReview

Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia

by Brik A. Kochoian, Cassandra Bure and Stella M. Papa

Cells 2023, 12(23), 2754; https://doi.org/10.3390/cells12232754 - 30 Nov 2023

Cited by 1 | Viewed by 1942

Abstract

A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson’s disease (PD). Yet, LIDs remain a clinical challenge for the management of patients [...] Read more.

A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson’s disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies. Full article

(This article belongs to the Special Issue Neurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies)

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20 pages, 3016 KiB

Open AccessReview

Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View

by Nitesh Sanghai and Geoffrey K. Tranmer

Cells 2023, 12(18), 2318; https://doi.org/10.3390/cells12182318 - 20 Sep 2023

Cited by 9 | Viewed by 6526

Abstract

Neurodegenerative diseases (NDDs) like Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of [...] Read more.

Neurodegenerative diseases (NDDs) like Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration. Numerous interrelated pathways lead to the progression of neurodegeneration. We present evidence from the past pieces of literature for the most usual global convergent hallmarks like ageing, oxidative stress, excitotoxicity-induced calcium butterfly effect, defective proteostasis including chaperones, autophagy, mitophagy, and proteosome networks, and neuroinflammation. Herein, we applied a holistic approach to identify and represent the shared mechanism across NDDs. Further, we believe that this approach could be helpful in identifying key modulators across NDDs, with a particular focus on AD, PD, and ALS. Moreover, these concepts could be applied to the development and diagnosis of novel strategies for diverse NDDs. Full article

(This article belongs to the Special Issue Neurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies)

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19 pages, 965 KiB

Open AccessReview

Exploring New Mechanism of Depression from the Effects of Virus on Nerve Cells

by Xinxin Yu, Shihao Wang, Wenzheng Wu, Hongyuan Chang, Pufan Shan, Lin Yang, Wenjie Zhang and Xiaoyu Wang

Cells 2023, 12(13), 1767; https://doi.org/10.3390/cells12131767 - 3 Jul 2023

Cited by 6 | Viewed by 2937

Abstract

Depression is a common neuropsychiatric disorder with long-term recurrent depressed mood, pain and despair, pessimism and anxiety, and even suicidal tendencies as the main symptoms. Depression usually induces or aggravates the development of other related diseases, such as sleep disorders and endocrine disorders. [...] Read more.

Depression is a common neuropsychiatric disorder with long-term recurrent depressed mood, pain and despair, pessimism and anxiety, and even suicidal tendencies as the main symptoms. Depression usually induces or aggravates the development of other related diseases, such as sleep disorders and endocrine disorders. In today’s society, the incidence of depression is increasing worldwide, and its pathogenesis is complex and generally believed to be related to genetic, psychological, environmental, and biological factors. Current studies have shown the key role of glial cells in the development of depression, and it is noteworthy that some recent evidence suggests that the development of depression may be closely related to viral infections, such as SARS-CoV-2, BoDV-1, ZIKV, HIV, and HHV6, which infect the organism and cause some degree of glial cells, such as astrocytes, oligodendrocytes, and microglia. This can affect the transmission of related proteins, neurotransmitters, and cytokines, which in turn leads to neuroinflammation and depression. Based on the close relationship between viruses and depression, this paper provides an in-depth analysis of the new mechanism of virus-induced depression, which is expected to provide a new perspective on the mechanism of depression and a new idea for the diagnosis of depression in the future. Full article

(This article belongs to the Special Issue Neurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies)

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