Selective neuronal vulnerability in Parkinson disease

Nature reviews. Neuroscience, Год журнала: 2017, Номер 18(2), С. 101 - 113

Опубликована: Янв. 20, 2017

Язык: Английский

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Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

Frontiers in Pharmacology, Год журнала: 2020, Номер 11

Опубликована: Апрель 23, 2020

Alpha-synuclein (α-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD characterized by the loss of dopaminergic neuronal cells substantia nigra pars compacta and abnormal accumulation aggregation α-Syn form Lewy bodies neurites. More precisely, associated with dysfunctionality degeneration neurons PD. Moreover, mutations SNCA gene, which encodes α-Syn, cause familial forms are basis sporadic risk. Given role pathology PD, animal models that reflect widespread progressive formation aggregates different areas brain constitute valuable tool. Indeed, important for understanding molecular mechanisms might contribute to development validation new therapies. In absence faithfully reproduce human recent years, numerous based on have been generated. this review, we summarize main features pre-formed fibrils (PFFs) model recombinant adeno-associated virus vector (rAAV) mediated overexpression models, providing detailed comparative analysis both models. Here, discuss how each has contributed our advantages weakness them.Here, show injection PFFs rAAV lead pattern rodents. First, trigger body-like inclusions regions directly interconnected site, suggesting there an inter-neuronal transmission contrast, rAAV-mediated limits within transduced neurons. Second, phosphorylated obtained predominantly nuclear punctate appearance becomes diffuse along fibers, whereas cytoplasmic reminiscent

Язык: Английский

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Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve

Molecular Neurodegeneration, Год журнала: 2018, Номер 13(1)

Опубликована: Май 11, 2018

Intraneuronal α-synuclein (α-Syn) aggregates known as Lewy bodies (LBs) and the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) are pathological hallmarks Parkinson's disease (PD). Braak's hypothesis based on autopsy studies suggests that pathology initially occurs enteric nervous system (ENS) then travels retrogradely to dorsal motor nucleus vagus nerve (dmX), proceeding from there a caudo-rostral direction. Recent evidence α-Syn propagate between interconnected supports this hypothesis. However, is no direct demonstrating transmission ENS dmX SNpc. We inoculated preformed fibrils (PFFs) or phosphate-buffered saline (PBS) into mouse gastric wall analyzed progression pathology. The mice with PFFs, but not PBS, developed phosphorylated (p-α-Syn)–positive LB-like at 45 days postinoculation. This aggregate formation was completely abolished when vagotomy performed prior inoculation suggesting were induced via nerve. Unexpectedly, number containing p-α-Syn–positive decreased over time, further propagation beyond observed up 12 months P-α-Syn–positive also present myenteric plexus unlike patients PD, cell-type specificity those model. Conclusions: These results indicate PFF gastrointestinal tract can induce resembling very early other factors apparently required if PD be replicated animal

Язык: Английский

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Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis

Nature Neuroscience, Год журнала: 2019, Номер 22(8), С. 1248 - 1257

Опубликована: Июль 25, 2019

Язык: Английский

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α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies

Neuroscience Letters, Год журнала: 2019, Номер 709, С. 134316 - 134316

Опубликована: Июнь 3, 2019

Язык: Английский

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Initiation and propagation of α-synuclein aggregation in the nervous system

Molecular Neurodegeneration, Год журнала: 2020, Номер 15(1)

Опубликована: Март 6, 2020

The two main pathological hallmarks of Parkinson's disease are loss dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one most effective treatment for alleviating motor symptoms (Olanow, Mov Disord 34:812-815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) modulate basal ganglia circuit activity successfully alleviates some symptoms. MRI guided focused ultrasound subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez Lancet 17:54-63, 2018). However, date, there exists no that stops progression this disease. findings α-synuclein can be released from inherited through interconnected neural networks opened door discovering novel strategies prevent formation spread pathology with goal halting PD its tracks. This hypothesis based on discoveries pathologic aggregates induce endogenous protein adopt similar conformation, thus self-propagating. Phase I clinical trials currently ongoing test treatments such immunotherapy neuron extracellular aggregates. Although tremendous progress has been made understanding how forms spreads throughout brain, cell intrinsic factors also play critical role mechanisms increase levels, selective expression profiles distinct subtypes, mutations altered function proteins involved synthesis degradation, oxidative stress. Strategies should consider release propagation, mechanisms.

Язык: Английский

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α-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies

Neurology, Год журнала: 2022, Номер 99(5), С. 195 - 205

Опубликована: Июнь 3, 2022

Parkinson disease (PD) is the second most common neurodegenerative disease, and synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset progression. Although neuropathologic changes begin many years before of motor manifestations, diagnosis still relies on identification symptoms, which hinders to formulate early diagnosis. Because α-syn misfolding aggregation precede clinical possibility identify these phenomena patients with PD would allow us recognize at earliest, premotor phases, consequence transition from molecular Seed amplification assays (SAAs) are group techniques that currently support prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These enable detection minimal amounts prions CSF other matrices affected patients. Recently, SAAs have been successfully applied detect misfolded (α-syn) CSF, olfactory mucosa, submandibular gland biopsies, skin, saliva synucleinopathies. In categories, they can differentiate dementia Lewy bodies (DLBs) control subjects, even prodromal stages differential diagnosis, satisfactorily differentiated PD, DLB, multiple system atrophy (MSA) nonsynucleinopathy parkinsonisms. The kinetic analysis SAA fluorescence profiles allowed synucleinopathy-dependent fibrils conformations, commonly referred strains, demonstrated diagnostic potential differentiating among synucleinopathies, especially between body diseases (LBDs) (PD DLB) MSA. front highly promising data, make seeding activity detected by biomarker for there preanalytical analytical issues, mostly related assay standardization, need be solved. this review, we discuss key findings supporting application unmet needs, future perspectives.

Язык: Английский

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Alpha Synuclein: Neurodegeneration and Inflammation

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5914 - 5914

Опубликована: Март 21, 2023

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in pathogenesis Parkinson’s disease and related disorders, synucleinopathies, but also several other neurodegenerative disorders with a more elusive role. This review analyzes activities α-Syn, different conformational states, monomeric, oligomeric fibrils, relation to neuronal dysfunction. The damage induced by α-Syn various conformers will be analyzed its capacity spread intracellular aggregation seeds prion-like mechanism. In view prominent role inflammation virtually all activity illustrated considering influence on glial reactivity. We others have described interaction between general cerebral dysfunctional α-Syn. Differences microglia astrocyte activation been observed when vivo presence oligomers has combined lasting peripheral inflammatory effect. reactivity was amplified, while astrocytes were damaged double stimulus, opening new perspectives for control synucleinopathies. Starting from our studies experimental models, we extended perspective find useful pointers orient future research potential therapeutic strategies disorders.

Язык: Английский

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A topographical atlas of α-synuclein dosage and cell type-specific expression in adult mouse brain and peripheral organs

npj Parkinson s Disease, Год журнала: 2024, Номер 10(1)

Опубликована: Март 19, 2024

Parkinson's disease (PD) is the second most common neurodegenerative worldwide and presents pathologically with Lewy pathology dopaminergic neurodegeneration. contains aggregated α-synuclein (αSyn), a protein encoded by SNCA gene which also mutated or duplicated in subset of familial PD cases. Due to its predominant presynaptic localization, immunostaining for results diffuse reactivity pattern, providing little insight into types cells expressing αSyn. As result, αSyn expression-driven cellular vulnerability has been difficult ascertain. Using combination knock-in mice that target nucleus (Snca

Язык: Английский

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CNS implications of COVID-19: a comprehensive review

Reviews in the Neurosciences, Год журнала: 2020, Номер 32(2), С. 219 - 234

Опубликована: Дек. 7, 2020

Abstract COVID-19 was first reported in December 2019 the Wuhan city of China, and since then it has spread worldwide taking a heavy toll on human life economy. infection is commonly associated with symptoms like coughing, fever, shortness breath, besides, reports muscle pain, anosmia, hyposmia, loss taste are becoming evident. Recent suggest pathogenic invasion SARS-CoV-2 into CNS, that could thereby result devastating long term complications, primarily because some these complications may go unnoticed for time. Evidence virus enter CNS through angiotensin-converting enzyme-2 (ACE-2) receptor, neuronal transport, haematogenous route, nasal route via olfactory bulb, cribriform plate, propagates trans-synaptic signalling, shows retrograde movement along nerve fiber. induces inflammation neurological degenerative damage diverse mechanism which includes ACE-2 receptor damage, cytokine-associated injury or cytokine storm syndrome, secondary hypoxia, demyelination, blood–brain barrier disruption, neurodegeneration, neuroinflammation. Viral been to show association Parkinsonism, Alzheimer’s disorder, meningitis, encephalopathy, anxiety, depression, psychiatric symptoms, seizures, stroke, etc. This review provides detailed discussion pathogenesis COVID-19. Authors conclude cannot just be considered as disorder pulmonary peripheral system, rather significant involvement. Therefore, aspects should monitored very closely prevent even after patient recovered from

Язык: Английский

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