Biology subjects

Rocha, E. M.

Publications and source records attributed to Rocha, E. M..

4 recordsLinked to original sources

bioRxiv2026

AI-guided analysis of human pancreatic islet sociology reveals distinct cell compositional changes in type 1 diabetes

Human pancreatic islets exhibit greater anatomic and cellular heterogeneity than previously appreciated, raising fundamental questions about how their composition varies with age, sex, region, and islet size and how type 1 diabetes (T1D) alters these relationships. Yet these questions remained largely unresolved due to the bottleneck of manual tissue inspection. Here, we developed an integrated artificial intelligence (AI)-guided imaging, processing, and statistical pipeline enabling unbiased, high-throughput analysis of more than 2 million candidate islets from 106 non-diabetic (ND) and T1D donors. We identified age-, region-, sex-, and islet size-dependent differences in islet distribution and composition between ND and T1D donors. Profound {beta}-cell loss in T1D was accompanied by reciprocal -cell expansion, whereas {delta}-cells and pancreatic polypeptide cells were largely resilient. Cell area and pseudotime analyses uncovered regional and age-dependent trajectories of islet remodeling across T1D progression, along with distinct patterns of cytoarchitectural reorganization of the endocrine pancreas.

pathology↗

bioRxiv2024

Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in a rotenone rat model of Parkinson's disease

Pesticide exposure is increasingly recognised as a potential environmental factor contributing to the onset of idiopathic Parkinsons disease, yet the molecular mechanisms underlying this connection remain unclear. This study aims to explore how pesticide exposure disrupts key brain regions involved in Parkinsons disease pathology by reshaping gene regulatory landscapes. Using the well-established rotenone rat model of the disease, we performed H3K27ac ChIP-sequencing to profile active regulatory elements in the substantia nigra and cortex. In this model, rotenone distributes uniformly throughout the brain, and the degree of complex I inhibition is equivalent in cortical and substantia nigra neurons. Despite the uniformity of complex I inhibition, we identified widespread epigenomic differences, with brain region specific acetylation patterns associated with rotenone exposure. We showed consistent changes in transcriptomic activity by RNA-sequencing. Our results indicate there is a strong immune response to rotenone localised to the substantia nigra and highlight an enrichment of immune-related motifs in this brain region, suggesting that the immune response is at least partially driven by gene regulatory mechanisms. We also noted an increase in C1q complement pathway activity in the substantia nigra. In contrast, we identified widespread dysregulation of synaptic function at the gene regulatory level in the cortex of these same rats. Our results highlight a role for gene regulatory mechanisms potentially mediating the effects of pesticide exposure, driving region-specific functional responses in the brain that may contribute to the pathology and selective vulnerability that characterise Parkinsons disease.

genomics↗

bioRxiv2020

The industrial solvent trichloroethylene induces LRRK2 kinase activity and dopaminergic neurodegeneration in a rat model of Parkinson's disease

Gene-environment interaction is implicated in the majority of idiopathic Parkinsons disease (PD) risk, and some of the most widespread environmental contaminants are selectively toxic to dopaminergic neurons. Pesticides have long been connected to PD incidence, however, it has become increasingly apparent that other industrial byproducts likely influence neurodegeneration. For example, organic solvents, which are used in chemical, machining, and dry-cleaning industries, are of growing concern, as decades of solvent use and their effluence into the environment has contaminated much of the worlds groundwater and soil. Like some pesticides, certain organic solvents, such as the chlorinated halocarbon trichloroethylene (TCE), are mitochondrial toxicants, which are collectively implicated in the pathogenesis of dopaminergic neurodegeneration. Recently, we hypothesized a possible gene-environment interaction may occur between environmental mitochondrial toxicants and the protein kinase LRRK2, mutations of which are the most common genetic cause of familial and sporadic PD. In addition, emerging data suggests that elevated wildtype LRRK2 kinase activity also contributes to the pathogenesis of idiopathic PD. To this end, we investigated whether chronic, systemic TCE exposure (200 mg/kg) in aged rats produced wildtype LRRK2 activation and influenced predegenerative dopaminergic dysfunction. Interestingly, we found that TCE not only induced LRRK2 kinase activity in the brain, but produced a significant dopaminergic lesion in the nigrostriatal tract, elevated oxidative stress, and caused endolysosomal dysfunction and protein accumulation (-synuclein). Together, these data suggest that TCE-induced LRRK2 kinase activity contributed to the selective toxicity of dopaminergic neurons. We conclude that gene-environment interactions between certain industrial contaminants and LRRK2 likely influence PD risk.

pharmacology and toxicology↗

bioRxiv2020

Protection from α-synuclein-induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20 in the rat midbrain

Dopaminergic neurons of the substantia nigra are selectively vulnerable to mitochondrial dysfunction, which is hypothesized to be an early and fundamental pathogenic mechanism in Parkinsons disease (PD). Mitochondrial function depends on the successful import of nuclear-encoded proteins, many of which are transported through the TOM20-TOM22 outer mitochondrial membrane import receptor machinery. Recent data suggests that post-translational modifications of -synuclein promote its interaction with TOM20 at the outer mitochondrial membrane and thereby inhibit normal protein import, which leads to dysfunction and death of dopaminergic neurons. As such, preservation of mitochondrial import in the face of -synuclein accumulation might be a strategy to prevent dopaminergic neurodegeneration, however, this is difficult to assess using current in vivo models of PD. To this end, we established an exogenous co-expression system, utilizing AAV2 vectors to overexpress human -synuclein and TOM20, individually or together, in the adult Lewis rat substantia nigra in order to assess whether TOM20 overexpression attenuates -synuclein-induced dopaminergic neurodegeneration. Twelve weeks after viral injection, we observed that AAV2-TOM20 expression was sufficient to prevent loss of nigral dopaminergic neurons caused by AAV2-Syn overexpression. The observed TOM20-mediated dopaminergic neuron preservation appeared to be due, in part, to the rescued import of nuclear-encoded mitochondrial electron transport chain proteins that were inhibited by -synuclein overexpression. In addition, TOM20 overexpression rescued the import of the chaperone protein GRP75/mtHSP70/mortalin, a stress-response protein involved in -synuclein-induced injury. Collectively, these data indicate that TOM20 expression prevents -synuclein-induced mitochondrial dysfunction, which is sufficient to rescue dopaminergic neurons in the adult rat brain.

neuroscience↗