Biology subjects

Semenyuk, O.

Publications and source records attributed to Semenyuk, O..

2 recordsLinked to original sources

bioRxiv2021

Spatiotemporal Control of Actomyosin Contractility by MRCKβ Signaling Drives Phagocytosis

Phagocytosis requires myosin-generated contractile force to regulate actin dynamics. However, little is known about the molecular mechanisms that guide this complex morphodynamic process. Here we show that particle binding to Mer Tyrosine Kinase (MerTK), a widely expressed phagocytic receptor, stimulates phosphorylation of the Cdc42 GEF Dbl3 in the retinal pigment epithelium (RPE), triggering activation of MRCK{beta} and its co-effector N-WASP that cooperate to deform the membrane into cups. Continued MRCK{beta} activity then drives recruitment of a mechanosensing bridge enabling transmission of the cytoskeletal force required for cup closure and particle internalization. MRCK{beta} is also required for Fc receptor-mediated phagocytosis by macrophages. In vivo, MRCK{beta} is essential for RPE phagocytosis of photoreceptor debris and, hence, retinal integrity. MerTK-independent activation of MRCK{beta} signaling by a phosphomimetic Dbl3 mutant rescues phagocytosis in retinitis pigmentosa RPE cells lacking functional MerTK. Thus, conserved MRCK{beta} signaling controls spatiotemporal regulation of actomyosin contractility to guide actomyosin dynamics-driven phagocytosis and represents the principle phagocytic effector pathway downstream of MerTK.

cell biology↗

bioRxiv2019

Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and preclinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

neuroscience↗