Biology subjects

Maciuca, R.

Publications and source records attributed to Maciuca, R..

4 recordsLinked to original sources

bioRxiv2026

CSF glucosylsphingosine is a central readout of GCase impairment across genetic and sporadic Parkinson’s disease

Parkinsons disease (PD) risk converges on lysosomal biology, including reduced activity of glucocerebrosidase (GCase), encoded by GBA1. Glucosylsphingosine (GlcSph), a toxic deacylated glycosphingolipid and established target engagement biomarker in Gaucher disease, is difficult to quantify in cerebrospinal fluid (CSF) because of low abundance and isomeric interference. We optimized and qualified targeted LC-MS/MS assays for GlcSph in CSF and plasma and measured GlcSph and GCase activity (4-MU assay) in participants from the Parkinsons Progression Markers Initiative (PPMI), including GBA1 and LRRK2 mutation carriers with and without PD, sporadic PD, and healthy controls. Group level analyses showed higher levels of CSF and plasma GlcSph in GBA1 heterozygous variant carriers independent of disease status, [~]120% (p<0.0001) and [~]61% (p<0.0001), respectively, with CSF elevations reflecting allelic dosage and, to a lesser degree, variant severity. Notably, elevated CSF GlcSph was observed not only in carriers of pathogenic GBA1 mutations but also in individuals harboring common GBA1 risk variants. CSF GlcSph was also elevated by [~]30% in sporadic PD (p=0.002) and by [~]40% LRRK2 mutation carriers (p=0.0003), indicating shared central GCase pathway perturbation across PD subtypes. CSF and plasma GlcSph levels showed poor concordance across groups with the exception of the GBA-PD group, supporting the hypothesis that central and peripheral GCase pathway dysfunction arise through distinct biological mechanisms. Together, these findings establish CSF GlcSph as a sensitive biomarker of central GCase pathway impairment and may support its use as a pharmacodynamic and target engagement biomarker for therapeutics targeting GCase in PD. More broadly, CSF GlcSph may enable identification of biologically defined GCase-pathway dysfunction beyond genetically defined GBA1-associated PD, with potential implications for patient stratification in future disease-modifying trials.

Molecular Biology↗

bioRxiv2023

DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models - the optic nerve crush injury and an eIF2B loss of function (LOF) mutant - demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.

neuroscience↗

bioRxiv2022

LRRK2 Kinase Activity Regulates Parkinson's Disease-Relevant Lipids at the Lysosome

Lysosomal dysfunction is a hallmark of Parkinsons disease (PD), and variants in several PD-associated genes, including LRRK2, perturb lysosomal homeostasis. Based on this, LRRK2 kinase inhibition is being explored as a therapeutic approach for the treatment of PD. LRRK2 inhibitors reduce levels of BMP, an endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in urine from preclinical models and clinical subjects, however, the mechanisms by which LRRK2 regulates BMP and the functional significance of this change to disease are undefined. We establish that LRRK2 regulates secretion of BMP- and GSL-containing vesicles from kidney into urine and modulates BMP and GSL levels in the brain. BMP accumulates within lysosomes as a secondary response to LRRK2s effects on the activity of glucocerebrosidase (GCase), a PD-linked enzyme involved in GSL catabolism. Alterations in BMP and GCase substrate turnover are observed in CSF from LRRK2-PD patients, highlighting the relevance of LRRK2-dependent lysosomal dysfunction in disease.

neuroscience↗

bioRxiv2021

Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pRab10

Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinsons disease (PD). Pathogenic variants in LRRK2, including the common variant G2019S, result in increased LRRK2 kinase activity, supporting the therapeutic potential of LRRK2 kinase inhibitors for PD. To better understand the role of LRRK2 in disease and to support the clinical development of LRRK2 inhibitors, quantitative and high-throughput assays to measure LRRK2 levels and activity are needed. We developed and applied such assays to measure the levels of LRRK2 as well as the phosphorylation of LRRK2 itself or one of its substrates, Rab10 (pT73 Rab10). We observed increased LRRK2 activity in various cellular models of disease, including iPSC-derived microglia, as well as in human subjects carrying disease-linked variant in LRRK2 (G2019S). Capitalizing on the high-throughput and sensitive nature of these assays, we detected a significant reduction in LRRK2 activity in subjects carrying missense variants in LRRK2 associated with reduced disease risk. Finally, we optimized these assays to enable analysis of LRRK2 activity following inhibition in human peripheral blood mononuclear cells (PBMCs) and whole blood, demonstrating their potential utility as biomarkers to assess changes in LRRK2 expression and activity in the clinic.

neuroscience↗