Niemann-Pick Type C Disease Reveals a Link between Lysosomal Cholesterol and PtdIns(4,5)P2 That Regulates Neuronal Excitability.

There is increasing evidence that the lysosome is involved in the pathogenesis of a variety of neurodegenerative disorders. Thus, mechanisms that link lysosome dysfunction to the disruption of neuronal homeostasis offer opportunities to understand the molecular underpinnings of neurodegeneration and potentially identify specific therapeutic targets. Here, using a monogenic neurodegenerative disorder, NPC1 disease, we demonstrate that reduced cholesterol efflux from lysosomes aberrantly modifies neuronal firing patterns. The molecular mechanism linking alterations in lysosomal cholesterol egress to intrinsic tuning of neuronal excitability is a transcriptionally mediated upregulation of the ABCA1 transporter, whose PtdIns(4,5)P2-floppase activity decreases plasma membrane PtdIns(4,5)P2. The consequence of reduced PtdIns(4,5)P2 is a parallel decrease in a key regulator of neuronal excitability, the voltage-gated KCNQ2/3 potassium channel, which leads to hyperexcitability in NPC1 disease neurons. Thus, cholesterol efflux from lysosomes regulates PtdIns(4,5)P2 to shape the electrical and functional identity of the plasma membrane of neurons in health and disease

Spontaneous locomotion of a symmetric squirmer

The squirmer is a popular model to analyse the fluid mechanics of a self-propelled object, such as a micro-organism. We demonstrate that some fore-aft symmetric squirmers can spontaneously self-propel above a critical Reynolds number. Specifically, we numerically study the effects of inertia on axisymmetric squirmers characterised by a 'quadrupolar' fore-aft symmetric distribution of surface-slip velocity; under creeping-flow conditions, such squirmers generate a pure stresslet flow, the stresslet sign classifying the squirmer as either a 'pusher' or 'puller.' Assuming axial symmetry, and over the examined range of the Reynolds number $Re$ (defined based upon the magnitude of the quadrupolar squirming), we find that spontaneous symmetry breaking occurs in the puller case above $Re \approx 14.3$, with steady swimming emerging at the threshold via a supercritical pitchfork bifurcation, beyond which the swimming speed grows monotonically with $Re$