Biology subjects

Erb, M. L.

Publications and source records attributed to Erb, M. L..

3 recordsLinked to original sources

bioRxiv2026

System-wide profiling reveals metabolic alterations in a G2019S LRRK2 knockin mouse model of Parkinson's disease: systemic depletion of pyrimidine nucleosides

G2019S LRRK2 is the most common cause of familial Parkinsons disease (PD) and is associated with sporadic PD, arising from the interplay of genetic predisposition, environmental exposure and aging. Metabolic syndrome is implicated as a risk factor for PD, but the interaction between G2019S LRRK2 and metabolic stress in disease pathogenesis remains unclear. We employed high-fat diet (HFD) feeding to induce metabolic syndrome in aged mutant LRRK2 mice, followed by system-wide characterization, including metabolomic or proteomic profiling, and bulk or single-nucleus RNA sequencing. We find that thymidine and deoxyuridine levels are consistently reduced across tissues in G2019S LRRK2 knockin mice accompanied by increased hepatic expression of thymidine phosphorylase. HFD exposure further unmasks disruptions in purine and energy metabolism in brain and lung of G2019S LRRK2 knockin mice, with midbrain astrocytes and oligodendrocytes exhibiting the most pronounced impairment in oxidative phosphorylation transcriptional pathways. Our findings demonstrate that pre-existing metabolic syndrome unmasks widespread disruptions in systemic nucleotide and energy metabolism and exacerbates mitochondrial dysfunction in G2019S LRRK2 knockin mice. This conditional "two-hit" phenotype underscores the critical role of environmental factors, such as diet, in revealing metabolic vulnerabilities associated with PD-linked genetic backgrounds, and provides potential metabolic targets for therapeutic intervention in PD.

neuroscience↗

bioRxiv2024

Adult-Onset Deletion of ATP13A2 in Mice Induces Progressive Nigrostriatal Pathway Dopaminergic Degeneration and Lysosomal Abnormalities

Although most cases of Parkinsons disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of PD. A surprising number of familial PD-linked genes and PD risk genes are involved in intracellular trafficking and protein degradation. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome (KRS), hereditary spastic paraplegias (HSPs), neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis (ALS). Given the severe effects of ATP13A2 mutations in humans, it is surprising that ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages. This discrepancy between human subjects and rodents makes it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.

neuroscience↗

bioRxiv2021

Principles of ecDNA random inheritance drive rapid genome change and therapy resistance in human cancers

The foundational principles of Darwinian evolution are variation, selection, and identity by descent. Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumour growth, drug resistance, and shorter survival in patients1-4. Currently, the impact of non-chromosomal oncogene inheritance--random identity by descent--is not well understood. Neither is the impact of ecDNA on variation and selection. Here, integrating mathematical modeling, unbiased image analysis, CRISPR-based ecDNA tagging, and live-cell imaging, we identify a set of basic "rules" for how random ecDNA inheritance drives oncogene copy number and distribution, resulting in extensive intratumoural ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted cancer treatment. Observed ecDNAs obligatorily benefit host cell survival or growth and can change within a single cell cycle. In studies ranging from well-curated, patient-derived cancer cell cultures to clinical tumour samples from patients with glioblastoma and neuroblastoma treated with oncogene-targeted drugs, we show how these ecDNA inheritance "rules" can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are entailed by their ability to rapidly change their genomes in a way that is not possible for cancers driven by chromosomal oncogene amplification. These results shed new light on how the non-chromosomal random inheritance pattern of ecDNA underlies poor outcomes for cancer patients.

cancer biology↗