Biology subjects

Ollendorff, M. K.

Publications and source records attributed to Ollendorff, M. K..

3 recordsLinked to original sources

bioRxiv2025

The SorCS2-derived macrocycle TT-P34 drives neuroprotection in animal models of neurodegeneration

Mitochondria are critical for sustaining the high energy demands of neuronal activity and their dysregulation is a hallmark of neurodegeneration. Targeting pathways of neurotrophic signaling is a well-established therapeutic strategy to enhance mitochondrial function and mitigate neurodegeneration. The VPS10p domain receptor, SorCS2, has recently emerged as a receptor with neurotrophic signaling capabilities. Here, we design and develop novel SorCS2-derived macrocyclic peptides mimicking receptor activation in vivo. We show that SorCS2-peptides enhance both neurotrophic support and boost metabolism by activating CREB and AMPK in a CAMKK2-dependent manner. This leads to upregulation of the key transcription factors PGC1 and TFEB and consequentially mitochondrial biogenesis. Furthermore, we show that the lipidated SorCS2 macrocycle, TT-P34, rescues motor behavioral deficits and preserves synaptic and mitochondrial signatures in the zQ175 mouse model of Huntingtons Disease. In addition, treating a MPTP-induced mouse model of Parkinsons Disease leads to amelioration of behavioral deficits and reduction of dopaminergic loss. Finally, we demonstrate that TT-P34 crosses the blood-brain barrier in non-human primates, and estimate human therapeutic dosing by pharmacodynamic modelling. Together, our findings support the use of TT-P34 as a novel disease-modifying therapy targeting SorCS2-receptor signaling to prevent neurodegeneration.

neuroscience↗

bioRxiv2025

Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation

The leukocyte common antigen related receptor (LAR) is a member of the LAR receptor protein tyrosine phosphatase (RPTP) family of synaptic adhesion molecules that contribute to the proper alignment and specialization of synaptic connections in the mammalian brain. LAR-RPTP members have been genetically associated with neuropsychiatric disorders, but the molecular consequences of genetic perturbations of LAR remain unstudied. Using exome sequencing data from psychiatric patients and controls, we identify rare missense variants of LAR that render the extracellular domain (ECD) unstable and susceptible to proteolytic cleavage. Using recombinant and cellular systems, we describe three variants that cause disruption of the LAR:NGL-3 interaction, which results in loss of transcellular adhesion and synaptogenic effects. Furthermore, we show that overexpression of two of these variants elicit altered morphological phenotypes in an imaging-based morphological profiling assay compared to wild type LAR, suggesting that destabilization of the LAR ECD has broad effects on LAR function. In conclusion, our study identifies three rare, missense variants in LAR that could provide insights into LAR involvement with psychiatric pathobiology.

neuroscience↗

bioRxiv2024

A triple serine motif in the intracellular domains of sortilin-related receptors SorCS1-3 regulates neurotrophic activity

The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS1-3 intracellular domains (ICDs) contain a conserved triple serine motif that potentially functions as a signaling switch to induce neurotrophic signaling in hippocampal neurons. We demonstrate that phosphorylation mimicking mutations of the SorCS1-3 triple serine motifs display neurotrophic activity independently of both their extracellular domains (ECDs) and BDNF, and that the substitution of serines to alanines renders neurons less responsive to BDNF. Hence, we develop triple serine motif-based cell-penetrating peptides that modulate downstream signaling kinases of the BDNF pathway, ultimately activating the transcription factor CREB. Taken together, we provide the first mechanistic insights into SorCS1-3 mediated neurotrophic signaling and use this knowledge to develop pharmacologically active modulators.

neuroscience↗