Biology subjects

van der Kant, R.

Publications and source records attributed to van der Kant, R..

3 recordsLinked to original sources

bioRxiv2025

Protective ApoE variants support neuronal function by extracting peroxidated lipids

ApoE mediates the transport of lipids from neurons to glial lipid droplets. ApoE4, a major risk factor for Alzheimer's disease, impairs this transport pathway, increasing risk for neurodegeneration. ApoE2 and ApoE3 Christchurch (ApoE3Ch) variants confer resistance to developing the disease, yet little is known regarding how these protective variants affect lipid transport. Here, we explored how lipoprotein particles containing different ApoE isoforms affect neuronal health in vitro and in intact rodent hippocampi. We demonstrate that ApoE2 and ApoE3Ch particles protect neurons from ferroptosis by preferentially extracting peroxidated unsaturated lipids through the neuronal ABCA7 transporter. ApoE4 particles, on the other hand, exacerbate the effects of these toxic lipids leading to endolysosomal dysfunction. By reducing the peroxidated lipid burden in ApoE4 neurons, ApoE2 and ApoE3Ch particles rescue endolysosomal function and restore defects in neuronal activity. Our findings reveal a new mechanism by which ApoE2 and ApoE3Ch isoforms protect neurons from neurodegenerative disease.

neuroscience↗

bioRxiv2024

Directed disruption of IL2 aggregation sites produces designer biologics with enhanced specificity coupled to improved production capacity

The pleotropic nature of interleukin-2 (IL2) has allowed it to be used as both a pro-inflammatory and anti-inflammatory therapeutic agent, through promotion of regulatory T cell (Treg) responses via the IL2RA receptor or promotion of CD8 T cell responses via the IL2RB receptor, respectively. However, the utility of IL2 as a treatment is limited by this same pleiotropy, and protein engineering to bias specificity towards either the regulatory T cell (Treg) or CD8 T cell lineage often requires a trade-off in protein production or total bioactivity. Here we use SolubiS, a computational algorithm-based method, to predict mutations within the IL2 structure to improve protein production yield while altering cellular selectivity, to generate a mutein with elevated therapeutic potential. The design and testing process identified the V126R (murine) / V111R (human) mutation as a Treg-enhancing mutein, creating a cation repulsion to inhibit primary binding to IL2RB, with a post-IL2RA confirmational shift enabling secondary IL2RB binding, and hence allowing the trimeric receptor complex to form. In human IL2, additional N110R T151R aggregation-protecting mutations could improve protein yield of the V111R mutation. The approach also generated novel CD8 T cell-promoting mutations. Y79K created a cation-cation repulsion with IL2RA, while Q50W enhanced CD8 T cell activity through potential {pi}-stacking enhancing binding to IL2RB, with the combination highly stimulatory for CD8 T cells. For human IL2, Y65K (homolog to murine Y79K) coupled with E82K prevented IL2RA binding, however it required the aggregation-protecting mutations of N110R T151R to rescue production. These muteins, designed with both cellular specificity and protein production features, have potential as both biological tools and therapeutics.

immunology↗

bioRxiv2024

Neuronal polyunsaturated fatty acids are protective in FTD/ALS

We report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in human post-mortem ALS spinal cord and a Drosophila model of the most common genetic cause of FTD/ALS, a repeat expansion in C9orf72. To investigate lipid alterations, we performed lipidomics on C9FTD/ALS iPSC-neurons and post-mortem FTLD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). To determine whether this PUFA deficit contributes to neurodegeneration, we fed C9FTD/ALS flies PUFAs, which yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of the C9orf72 flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor induced neuronal death in C9FTD/ALS patient iPSC-neurons. These data implicate neuronal fatty acid saturation in the pathogenesis of FTD/ALS and suggest that interventions to increase PUFA levels specifically within neurons will be beneficial.

neuroscience↗