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Biology subjects

Ahlawat, S.

Publications and source records attributed to Ahlawat, S..

2 recordsLinked to original sources

Preferential transport of synaptic vesicles across neuronal branches is regulated by the levels of the anterograde motor UNC-104/KIF1A

Asymmetric transport of cargo across axonal branches is a field of active research. Mechanisms contributing to preferential cargo transport along specific branches in vivo in wild type neurons are poorly understood. We find that anterograde synaptic vesicles preferentially enter the synaptic branch or pause at the branch point in C. elegans PLM neurons. The anterograde motor UNC-104/KIF1A regulates this vesicle behaviour at the branch point. Reduced levels of functional UNC-104 cause vesicles to predominantly pause at the branch point and lose their preference for turning into the synaptic branch. SAM- 4/Myrlysin, which aids in recruitment/activation of UNC-104 on synaptic vesicles, regulates vesicle behaviour at the branch point similar to UNC-104. Increasing the levels of UNC-104 increases the preference of vesicles to go straight towards the asynaptic end. This suggests that the neuron optimises UNC-104 levels on the cargo surface to maximise the fraction of vesicles entering the branch and minimise the fraction going to the asynaptic end.

cell biology↗

α-Synuclein aggregation intermediates form fibril polymorphs with distinct prion-like properties

-Synuclein (-Syn) amyloid fibrils in synucleinopathies (such as Parkinsons disease (PD), multiple system atrophy (MSA)) are structurally and functionally different, reminiscent of prion-like strains. However, how a single protein can form different fibril polymorphs in various synucleinopathies is not known. Here, we demonstrate the structure-function relationship of two distinct -Syn fibril polymorphs, the pre-matured fibrils (PMF) and helix-matured fibrils (HMF) based on -Syn aggregation intermediates. These polymorphs not only display the structural differences, including their fibril core structure as demonstrated by solid-state nuclear magnetic resonance (NMR) spectroscopy and H/D-exchange coupled with mass spectrometry but also possess different cellular activities such as seeding, cellular internalization, and cell-to-cell transmission. The HMF with a compact core structure exhibits low seeding potency in cells but readily internalizes and transmits from one cell to another. Whereas the less structured PMF lacks the cell-to-cell transmission ability but induces abundant -Syn pathology and triggers the formation of aggresomes in cells. Overall, the study highlights how the conformational heterogeneity in the aggregation pathway may lead to fibril polymorphs with distinct prion-like behavior in PD.

neuroscience↗