Brown, H. C. | Search bioRxiv

bioRxiv2025

Neuroprotective Parkinson's Disease Therapeutic: Transition Metal Dichalcogenide Nanoflower Treatments Alleviate Pathological Cell Stress

Parkinsons disease (PD) is triggered by irreversible degeneration of dopaminergic neurons in the midbrain, hypothalamus, and thalamus. Although the underlying molecular etiology of these pathological processes remains unclear, progressive aggregation of alpha-synuclein (-syn) and mitochondrial dysfunction are two expected mechanisms implicated in neuronal degeneration. Accumulating evidence indicates that transition metal dichalcogenide (TMD) nanoflowers (NFs), a novel class of nanomaterials, can restore mitochondrial health by the activation of mitochondrial biogenesis. However, therapeutic potential of TMD NFs in PD remains unclear. The current study investigates the neuroprotective properties of molybdenum disulfide (MoS2) and molybdenum diselenide (MoSe2) nanoflowers (NFs) in neurons and astrocytes exposed to -syn aggregates. It was found that MoS2 and MoSe2 suppressed -syn-induced unfolded protein response (UPR) in the endoplasmic reticulum, and upregulated autophagy and exocytosis of -syn fibrils. TMD NFs also reversed -syn-induced damage of cell mitochondria, simultaneously stimulating mitochondrial biogenesis. As a result, a drastic decrease in ROS levels in both neurons and astrocytes was observed. These results show that MoS2 or MoSe2 NFs could fully rescue neurons and astrocytes from the cytotoxic effects of -syn fibrils. Neuroprotective properties of these novel nanomaterials were further explored in Caenorhabditis elegans that overexpress -syn. Nematodes that received NFs experienced a drastic reduction in the amount of aggregated -syn which resulted in a significant increase in C. elegans lifespan. These findings indicated that MoS2 or MoSe2 NFs could be used as novel therapeutic to decelerate the progression of PD.

neuroscience↗

bioRxiv2021

Antibody-mediated depletion of human CLEC-2 in a novel humanised mouse model

Platelet C-type lectin-like receptor 2 (CLEC-2) has been proposed as a potential anti-thrombotic target as genetic or antibody-mediated receptor deficiency prevents occlusive thrombus formation in mice. This occurs through interaction with an unknown ligand as the endogenous ligand podoplanin is not present in the vasculature. However, the CLEC-2-podoplanin interaction does have an important role in tumour metastasis. There are currently no methods to test potential human therapeutics targeting CLEC-2, such as antibodies, in vivo. We have therefore generated and characterised a humanised CLEC-2 mouse (hCLEC-2KI) and developed a novel monoclonal anti-human CLEC-2 antibody, HEL1, for in vivo testing. hCLEC-2KI mice were phenotypically normal and had comparable platelet glycoprotein receptor expression, activation and aggregation to wildtype platelets. hCLEC-2KI mice had both comparable bleeding and vessel occlusion times to WT mice. Challenging hCLEC-2KI mice with HEL1 or a second monoclonal anti-hCLEC-2 antibody, AYP1, resulted in transient thrombocytopenia as well as CLEC-2 depletion for more than 2 weeks but had no effect on haemostasis. This illustrates the power of the humanised CLEC-2 mouse model in evaluating novel therapeutics in vivo, including antibodies that target CLEC-2, as well as the limited effect on haemostasis when targeting CLEC-2.

physiology↗