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Parkinson’s disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson’s disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson’s disease. Generation of a midbrain-striatum assembloid with progerin overexpression as an in vitro model of possessing aging and senescence characteristics for studying Parkinson’s disease.

The goal of understanding the architecture of neural circuits at the synapse level with a brain-wide perspective has powered the interest in high-speed and large field-of-view volumetric imaging at subcellular resolution. Here, we developed a method combining tissue expansion and light-sheet fluorescence microscopy to allow extended volumetric super resolution high-speed imaging of large mouse brain samples. We demonstrate the capabilities of this method by performing two color fast volumetric super resolution imaging of mouse CA1 and dentate gyrus molecular-, granule cell-, and polymorphic layers. Our method enables an exact evaluation of granule cell and neurite morphology within the context of large cell ensembles spanning several orders of magnitude in resolution. We found that imaging a brain region of in super resolution using light-sheet fluorescence expansion microscopy is about 17-fold faster than imaging the same region by a current state-of-the-art high-resolution confocal laser scanning microscope.

BackgroundPrevious studies in mouse, Xenopus and zebrafish embryos show strong tfap2e expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the role of human transcription factor activator protein 2 (TFAP2E) in human embryonic central nervous system (CNS), orofacial and maxillofacial development is unknown.MethodsThrough a collaborative work, exome survey was performed in families with congenital CNS, orofacial and maxillofacial anomalies. Exome variant prioritisation prompted TFAP2E gene for functional analysis in zebrafish embryos. Embryonic morphology and development were assessed after antisense morpholino (MO) knockdown (KD), CRISPR/Cas9 knockout and overexpression of tfap2e in fluorescent zebrafish reporter lines using in vivo microscopy. Computational structural protein modelling of the identified human variants was performed.ResultsIn total, exome survey identified novel or ultra-rare heterozygous missense variants in TFAP2E in seven individuals from five independent families with predominantly CNS, orofacial and maxillofacial anomalies. One variant was found de novo and another variant segregated in an affected multiplex family. Protein modelling of the identified variants indicated potential distortion of TFAP2E in the transactivation or dimerisation domain. MO KD and CRISPR/Cas9 knockout of tfap2e in zebrafish revealed hydrocephalus and a significant reduction of brain volume, consistent with a microencephaly phenotype. Furthermore, mRNA overexpression of TFAP2E indicates dosage-sensitive phenotype expression. In addition, zebrafish showed orofacial and maxillofacial anomalies following tfap2e KD, recapitulating the human phenotype.ConclusionOur human genetic data and analysis of Tfap2e manipulation in zebrafish indicate a potential role of TFAP2E in human CNS, orofacial and maxillofacial anomalies.

Parkinson’s disease (PD), one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to disease’s phenotypes. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early phenotypes of PD. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD.

Neurotensin-polyplex nanoparticles provide efficient gene transfection of nigral dopaminergic neurons when intracerebrally injected in preclinical trials of Parkinson’s disease because they do not cross the blood–brain barrier (BBB). Therefore, this study aimed to open BBB with focused ultrasound (FUS) on the substantia nigra to attain systemic and intranasal transfections and evaluate its detrimental effect in rats. Systemically injected Evans Blue showed that a two-pulse FUS opened the nigral BBB. Accordingly, 35 μL of neurotensin-polyplex nanoparticles encompassing the green fluorescent protein plasmid (79.6 nm mean size and + 1.3 mV Zeta-potential) caused its expression in tyrosine hydroxylase(+) cells (dopaminergic neurons) of both substantiae nigrae upon delivery via internal carotid artery, retro-orbital venous sinus, or nasal mucosa 30 min after FUS. The intracarotid delivery yielded the highest transgene expression, followed by intranasal and venous administration. However, FUS caused neuroinflammation displayed by infiltrated lymphocytes (positive to cluster of differentiation 45), activated microglia (positive to ionized calcium-binding adaptor molecule 1), neurotoxic A1 astrocytes (positive to glial fibrillary acidic protein and complement component 3), and neurotrophic A2 astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10), that ended 15 days after FUS. Dopaminergic neurons and axonal projections decreased but recuperated basal values on day 15 after transfection, correlating with a decrease and recovery of locomotor behavior. In conclusion, FUS caused transient neuroinflammation and reversible neuronal affection but allowed systemic and intranasal transfection of dopaminergic neurons in both substantiae nigrae. Therefore, FUS could advance neurotensin-polyplex nanotechnology to clinical trials for Parkinson’s disease.

Possible ionospheric effects of the Morelian meteoroid that passed and exploded over Mexico on 19 February 2020 (18 February 2020 local time) were estimated. The meteoroid trajectory, velocity and time of occurrence were calculated based on outdoor camera records. Modeling was used to estimate the meteoroid initial diameter, density, mass, velocity, energy and their change during its flight in the atmosphere. The ensemble of ionospheric scintillation indices calculated from the high-rate GNSS data and the filtered slant Total Electron Content data were used to reveal the presence of ionospheric disturbances generated by shock waves excited by the meteoroid flight and explosion. The first ionospheric responses to phenomena accompanying the meteoroid were detected (2.5–3.5) min after the explosion. The disturbances were attenuated quickly with distance from their source and were rarely recorded by GNSS receivers located more than 600 km from the meteoroid explosion site. The ionospheric disturbances of intermediate-scale, small-scale, shock-acoustic-wave-scale and sometimes medium-scale were revealed. The detected disturbances corresponded to the range of acoustic-gravity waves. An asymmetry of the disturbance manifestation in different directions was observed. The obtained results are in accordance with results of the observation of other meteoroids. Although the object was smaller and of less energy than other known meteoroids, it is an interesting case because, to the best of our knowledge, it isthe first known to us low-latitude meteoroid with the detected ionospheric effects.