Dysfunctional Autophagy and Endolysosomal System in Neurodegenerative Diseases: Relevance and Therapeutic Options

Autophagy and endolysosomal trafficking are crucial in neuronal development, function and survival. These processes ensure efficient removal of misfolded aggregation-prone proteins and damaged organelles, such as dysfunctional mitochondria, thus allowing the maintenance of proper cellular homeostasis. Beside this, emerging evidence has pointed to their involvement in the regulation of the synaptic proteome needed to guarantee an efficient neurotransmitter release and synaptic plasticity. Along this line, an intimate interplay between the molecular machinery regulating synaptic vesicle endocytosis and synaptic autophagy is emerging, suggesting that synaptic quality control mechanisms need to be tightly coupled to neurosecretion to secure release accuracy. Defects in autophagy and endolysosomal pathway have been associated with neuronal dysfunction and extensively reported in Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis among other neurodegenerative diseases, with common features and emerging genetic bases. In this review, we focus on the multiple roles of autophagy and endolysosomal system in neuronal homeostasis and highlight how their defects probably contribute to synaptic default and neurodegeneration in the above-mentioned diseases, discussing the most recent options explored for therapeutic interventions.

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Proteome Linked Biochemical Targets: Can Repair Defective Cellular Physiological Mechanisms?

Cellular Physiology and Biochemistry ◽

10.33594/000000350 ◽

2021 ◽

Vol 55 (S2) ◽

pp. 49-70

Keyword(s):

Neurodegenerative Diseases ◽

Natural Compound ◽

Neuronal Development ◽

Current Knowledge ◽

Cost Effective ◽

Protein Aggregates ◽

Natural Compounds ◽

Therapeutic Interventions ◽

Neuronal Homeostasis ◽

Neuronal Processes

Major cause of proteopathies is the accumulation of unwanted mutant and aberrant proteins. We know that imperfect ageing is one of chief risk factor for most neurodegenerative diseases. Neurodegenerative diseases are characterized by mutant misfolded protein aggregates developing neural stress and debilitating several neuronal processes. Reducing the levels of these abnormal proteins using various natural compounds can be a promising possible therapeutic strategy. But the advancement of natural compound-based therapies in neurodegeneration and imperfect ageing treatment has been impeded by different challenges and unknown molecular patho-mechansim. The complexity in the causative factors generating protein aggregates in neurons and their respective path towards cell death is high, making it a difficult to treat disorder. Several plant based compounds have proven to promote different neuronal homeostasis mechanisms. However, there is a pressing necessity to screen, find and develop cost-effective natural compound-based new therapeutic interventions which can be useful for clinical purposes in treating neurodegenerative ailments. It is critical to discuss and elaborate the applications of few important natural compounds and their connections with following mechanisms: protein disposal machineries, apoptosis, neuroinflammation, neuronal development, synaptogenesis and neural homeostasis. This article summarizes the current knowledge and discusses the unanswered questions linked with the natural compounds and their promising therapeutic avenues primarily focusing on neurodegenerative diseases and defective neurobiological mechanisms.

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BDNF-dependent modulation of axonal transport is selectively impaired in ALS

10.1101/2021.12.06.471484 ◽

2021 ◽

Author(s):

Andrew P. Tosolini ◽

James N. Sleigh ◽

Sunaina Surana ◽

Elena R. Rhymes ◽

Stephen D. Cahalan ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Axonal Transport ◽

Neuronal Development ◽

Therapeutic Interventions ◽

Wild Type ◽

Disease Pathogenesis ◽

Sciatic Nerves ◽

Lateral Sclerosis ◽

Selective Impairment ◽

Stimulation Of

AbstractAxonal transport ensures long-range delivery of essential cargoes between proximal and distal compartments of neurons, and is needed for neuronal development, function, and survival. Deficits in axonal transport have been detected at pre-symptomatic stages in mouse models of amyotrophic lateral sclerosis (ALS), suggesting that impairments are fundamental for disease pathogenesis. However, the precise mechanisms responsible for the transport deficits and whether they preferentially affect α-motor neuron (MN) subtypes remain unresolved. Here, we report that stimulation of wild-type neurons with brain-derived neurotrophic factor (BDNF) enhances trafficking of signalling endosomes specifically in fast MNs (FMNs). In early symptomatic SOD1G93A mice, FMNs display selective impairment of axonal transport and develop an insensitivity to BDNF stimulation, with pathology upregulating classical non-pro-survival receptors in muscles and sciatic nerves. Altogether, these data indicate that cell- and non-cell autonomous BDNF signalling is impaired in vulnerable SOD1G93A MNs, thus identifying a new key deficit in ALS amenable for future therapeutic interventions.

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Microglial Potassium Channels: From Homeostasis to Neurodegeneration

Biomolecules ◽

10.3390/biom11121774 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1774

Author(s):

Germana Cocozza ◽

Stefano Garofalo ◽

Riccardo Capitani ◽

Giuseppina D’Alessandro ◽

Cristina Limatola

Keyword(s):

Potassium Channels ◽

Neurodegenerative Diseases ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Cns Disorders ◽

Pathological Conditions ◽

Wide Range ◽

Functional Features ◽

Lateral Sclerosis

The growing interest in the role of microglia in the progression of many neurodegenerative diseases is developing in an ever-expedited manner, in part thanks to emergent new tools for studying the morphological and functional features of the CNS. The discovery of specific biomarkers of the microglia phenotype could find application in a wide range of human diseases, and creates opportunities for the discovery and development of tailored therapeutic interventions. Among these, recent studies highlight the pivotal role of the potassium channels in regulating microglial functions in physiological and pathological conditions such as Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis. In this review, we summarize the current knowledge of the involvement of the microglial potassium channels in several neurodegenerative diseases and their role as modulators of microglial homeostasis and dysfunction in CNS disorders.

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Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions

Journal of Neurodegenerative Diseases ◽

10.1155/2013/563481 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 27

Author(s):

Saba Sheikh ◽

Safia ◽

Ejazul Haque ◽

Snober S. Mir

Keyword(s):

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Drug Targets ◽

Molecular Mechanisms ◽

Therapeutic Interventions ◽

Conformational Diseases ◽

Considerable Evidence ◽

Recent Trends ◽

Lateral Sclerosis

Neurodegenerative diseases are multifactorial debilitating disorders of the nervous system that affect approximately 30 millionindividuals worldwide. Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis diseases are the consequence of misfolding and dysfunctional trafficking of proteins. Beside that, mitochondrial dysfunction, oxidative stress, and/or environmental factors strongly associated with age have also been implicated in causing neurodegeneration. After years of intensive research, considerable evidence has accumulated that demonstrates an important role of these factors in the etiology of common neurodegenerative diseases. Despite the extensive efforts that have attempted to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. However, in order to explore the therapeutic interventions directed towards treatment of neurodegenerative diseases, neuroscientists are now fully exploiting the data obtained from studies of these basic mechanisms that have gone awry. The novelty of these mechanisms represents a challenge to the identification of viable drug targets and biomarkers for early diagnosis of the diseases. In this paper, we are reviewing various aspects associated with the disease and the recent trends that may have an application for the treatment of the neurodegenerative disorders.

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Excitotoxicity as a Target Against Neurodegenerative Processes

Current Pharmaceutical Design ◽

10.2174/1381612826666200113162641 ◽

2020 ◽

Vol 26 (12) ◽

pp. 1251-1262 ◽

Cited By ~ 2

Author(s):

Octavio Binvignat ◽

Jordi Olloquequi

Keyword(s):

Neurodegenerative Diseases ◽

Effective Treatment ◽

Molecular Mechanisms ◽

Prolonged Exposure ◽

Mitochondrial Dysfunctions ◽

Beneficial Effects ◽

Clinical Investigations ◽

Turn Over ◽

Excitotoxic Cell Death ◽

Lateral Sclerosis

: The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation. : Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms. : In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.

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Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽

10.3390/biology10020163 ◽

2021 ◽

Vol 10 (2) ◽

pp. 163

Author(s):

Swapnil Gupta ◽

Panpan You ◽

Tanima SenGupta ◽

Hilde Nilsen ◽

Kulbhushan Sharma

Keyword(s):

Dna Repair ◽

Neurodegenerative Diseases ◽

3D Models ◽

Model Systems ◽

Spinocerebellar Ataxias ◽

C Elegans ◽

Cellular Processes ◽

Age Related ◽

Damage Response ◽

Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

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Different miRNA Profiles in Plasma Derived Small and Large Extracellular Vesicles from Patients with Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22052737 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2737

Author(s):

Daisy Sproviero ◽

Stella Gagliardi ◽

Susanna Zucca ◽

Maddalena Arigoni ◽

Marta Giannini ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Extracellular Vesicles ◽

Small Rnas ◽

Biomarker Discovery ◽

Toll Like Receptor ◽

Neurotrophin Signaling ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Lateral Sclerosis ◽

Glycosphingolipid Biosynthesis

Identifying biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different miRNA signatures in plasma derived LEVs and SEVs of Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients. LEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and differential centrifugation and RNA was extracted. Small RNAs libraries were carried out by Next Generation Sequencing (NGS). MiRNAs discriminate all NDs diseases from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were instead linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway. LEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading of the disease. The study of common and different miRNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration.

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Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease

Molecular Neurobiology ◽

10.1007/s12035-021-02489-5 ◽

2021 ◽

Author(s):

Marina Betancor ◽

Laura Moreno-Martínez ◽

Óscar López-Pérez ◽

Alicia Otero ◽

Adelaida Hernaiz ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Prion Disease ◽

Tetanus Toxin ◽

Neuronal Survival ◽

Prion Diseases ◽

Cellular Prion Protein ◽

Murine Models ◽

Terminal Fragment ◽

Lateral Sclerosis

AbstractThe non-toxic C-terminal fragment of the tetanus toxin (TTC) has been described as a neuroprotective molecule since it binds to Trk receptors and activates Trk-dependent signaling, activating neuronal survival pathways and inhibiting apoptosis. Previous in vivo studies have demonstrated the ability of this molecule to increase mice survival, inhibit apoptosis and regulate autophagy in murine models of neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of the cellular prion protein (PrPC) into an abnormal and misfolded isoform known as PrPSc. These diseases share different pathological features with other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson’s disease or Alzheimer’s disease. Hitherto, there are no effective therapies to treat prion diseases. Here, we present a pilot study to test the therapeutic potential of TTC to treat prion diseases. C57BL6 wild-type mice and the transgenic mice Tg338, which overexpress PrPC, were intracerebrally inoculated with scrapie prions and then subjected to a treatment consisting of repeated intramuscular injections of TTC. Our results indicate that TTC displays neuroprotective effects in the murine models of prion disease reducing apoptosis, regulating autophagy and therefore increasing neuronal survival, although TTC did not increase survival time in these models.

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Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis

Nature Communications ◽

10.1038/s41467-021-23691-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Maria Babu ◽

Filippo Favretto ◽

Alain Ibáñez de Opakua ◽

Marija Rankovic ◽

Stefan Becker ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Protein Folding ◽

Neurodegenerative Diseases ◽

Catalyst Activity ◽

Coding Region ◽

Prolyl Isomerase ◽

X Ray Crystallography ◽

Hexanucleotide Repeat ◽

Lateral Sclerosis ◽

Dipeptide Repeat

AbstractAmyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases.

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Molecular mechanisms of cell death in neurological diseases

Cell Death and Differentiation ◽

10.1038/s41418-021-00814-y ◽

2021 ◽

Author(s):

Diane Moujalled ◽

Andreas Strasser ◽

Jeffrey R. Liddell

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Neurological Diseases ◽

Treatment Strategies ◽

Current Treatment ◽

Response To Therapy ◽

Signalling Cascades ◽

The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

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