Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

Bernal-Conde, Luis Daniel; Ramos-Acevedo, Rodrigo; Reyes-Hernández, Mario A.; Balbuena-Olvera, Andrea Joselin; Morales-Moreno, Ishbelt D.; Argüero‐Sánchez, Rubén; Schüle, Birgitt; Guerra-Crespo, Magdalena

doi:10.3389/fnins.2019.01399

Cited by 125 publications

(122 citation statements)

References 240 publications

(326 reference statements)

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“…Pathologic α-syn can interfere with all these organelles, consequently impairing-related pathways. 86 , 87 The protein can change its conformation and aggregate, giving rise to oligomers, fibrils, and larger aggregates. 88 Which form is responsible for toxicity is still a matter of debate.…”

Section: Pathophysiology Of Synaptic Dysfunction and Lossmentioning

confidence: 99%

Fluid Biomarkers for Synaptic Dysfunction and Loss

et al. 2020

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Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer’s disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and α-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.

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Section: Pathophysiology Of Synaptic Dysfunction and Lossmentioning

confidence: 99%

Fluid Biomarkers for Synaptic Dysfunction and Loss

et al. 2020

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“…Mutational changes in the gene lead to diminished mitochondrial quality control and autosomal recessive PD [ 50 , 51 ]. Moreover, α-synuclein interferes with mitochondrial functions; for instance, it can react with mitochondrial membrane and aggregate in organelles [ 52 ]. α-synuclein prompts the damage of mitochondrial complex I roles and results in mitochondrial dysfunction and higher oxidative stress [ 53 , 54 ].…”

Section: Pathogenesis and Symptoms Of Pdmentioning

confidence: 99%

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Prasad

Hung

2020

Antioxidants

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Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson’s disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer’s disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms’ treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.

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“…Lewy body diseases include Parkinson's disease (PD), DLB, and multiple system atrophy. The pathological hallmarks of Lewy body diseases are the abnormal intracellular accumulation of Lewy bodies, which are composed of α-synuclein [81]. α-Synuclein is a 140-amino acid protein that is abundantly localized to presynaptic terminals.…”

Section: Lewy Body Diseases and Neurometalsmentioning

confidence: 99%

Amyloids: Regulators of Metal Homeostasis in the Synapse

2020

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Conformational changes in amyloidogenic proteins, such as β-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with β-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca2+-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca2+ homeostasis in amyloid-associated neurodegenerative diseases.

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Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

Cited by 125 publications

References 240 publications

Fluid Biomarkers for Synaptic Dysfunction and Loss

Fluid Biomarkers for Synaptic Dysfunction and Loss

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Amyloids: Regulators of Metal Homeostasis in the Synapse

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