VU Gyvybės mokslų centras jungia tris VU padalinius – Biomokslų, Biotechnologijos ir Biochemijos institutus. Centras įkurtas vystant integruotą mokslo, studijų ir verslo centrą (slėnį) „Saulėtekis“.

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The accumulation of the ganglioside GM2 can lead to gangliosidoses such as Tay-Sachs and Sandhoff diseases. This study develops a new, in vitro, neuron-based model of GM2 gangliosidoses, revealing cha...

Glycosphingolipids (GSL) are important bioactive components of cellular membranes. Complex GSLs, containing sialic acid residues are known as gangliosides and are highly abundant in the brain. Diseases of ganglioside metabolism often result in severe, early-onset neurodegeneration. The ganglioside GM2 is the substrate of the hydrolytic lysosomal β- hexosaminidase A (HexA) enzyme and when subunits of this enzyme are non-functional, GM2 lipid accumulates in cells leading to the GM2 gangliosidoses, Tay-Sachs and Sandhoff diseases. We have developed high-quality i3Neuron-based models of Tay-Sachs and Sandhoff diseases, that demonstrate storage of GM2, formation of membrane whorls and accumulation of endolysosomal proteins consistent with disease phenotypes. Importantly, in addition to lysosomal dysfunction, the composition of the plasma membrane (PM) is significantly impacted in these diseases with changes in the abundance of both lipids and proteins. The changes to the PM proteome are driven in part by exocytosis of lysosomal material resulting in the aberrant accumulation of lysosomal proteins and lipids on the cell surface. The altered abundance of GM2 at the PM was striking, bringing the abundance of this precursor lipid up to that of the common neuronal gangliosides. Furthermore, the PM profiling identifies significant changes in synaptic protein abundances with direct functional impact on neuronal activity including rapid electrical firing consistent with neuronal hyperactivity. This work provides mechanistic insights into neuronal dysfunction in the GM2 gangliosidoses and highlights that these are also severe PM disorders. This work has broad implications for other lysosomal storage disorders and late-onset neurodegenerative diseases involving sphingolipid dysregulation. ### Competing Interest Statement The authors have declared no competing interest.

Bacteria use toxic effectors to outcompete other bacteria, influencing the composition of microbial communities. This study shows that the cysteine protease Cpe1, a widespread toxin in Gram negative b...