No abstract

We investigated the transport of neuronal mitochondria using superlocalized near-fields with plasmonic nanohole arrays (PNAs). Compared to traditional imaging techniques, PNAs create a massive array of superlocalized light beams and allow 3D mitochondrial dynamics to be sampled and extracted almost in real time. In this work, mitochondrial fluorescence excited by the PNAs was captured by an optical microscope using dual objective lenses, which produced superlocalized dynamics while minimizing light scattering by the plasmonic substrate. It was found that mitochondria move with an average velocity 0.33 ± 0.26 μm/s, a significant part of which, by almost 50%, was contributed by the movement along the depth axis (z-axis). Mitochondrial positions were acquired with superlocalized precision (σ x = 5.7 nm and σ y = 11.8 nm) in the lateral plane and σ z = 78.7 nm in the z-axis, which presents an enhancement by 12.7-fold in resolution compared to confocal fluorescence microscopy. The approach is expected to serve as a way to provide 3D information on molecular dynamics in real time.

No abstract

Amyotrophic lateral sclerosis (ALS) is a severe disease causing motor neuron death, but a complete cure has not been developed and related genes have not been defined in more than 80% of cases. Here we compared whole genome sequencing results from a male ALS patient and his healthy parents to identify relevant variants, and chose one variant in the X-linked ATP7A gene, M1311V, as a strong disease-linked candidate after profound examination. Although this variant is not rare in the Ashkenazi Jewish population according to results in the genome aggregation database (gnomAD), CRISPR-mediated gene correction of this mutation in patient-derived and re-differentiated motor neurons drastically rescued neuronal activities and functions. These results suggest that the ATP7A M1311V mutation has a potential responsibility for ALS in this patient and might be a potential therapeutic target, revealed here by a personalized medicine strategy.

Highlights d Npas4 binds to the promoter of IQSEC3 and regulates its expression d Npas4 upregulates IQSEC3 expression in SST + interneurons d Npas4/IQSEC3-dependent inhibition of SST + interneurons controls anxiety-like behavior d The ARF-GEF activity of IQSEC3 is critical for its synaptic functions