Biology subjects

Rados, M.

Publications and source records attributed to Rados, M..

2 recordsLinked to original sources

bioRxiv2025

Distinct cerebrospinal fluid DNA methylation signatures linked to Alzheimer's disease

Alzheimers disease (AD) accounts for more than 60% of the dementia cases and currently there is no curative treatment for it. With the emergence of potentially disease modifying treatments, early diagnosis is key to identify patient groups that would benefit from such treatments, aiming to prevent severe cognitive decline. We previously identified a set of DNA methylation signatures that allow for accurate diagnosis of AD in cortical neurons and brain tissue, even before clinical manifestation of the disease [1]. Here we investigate 11 of these signature regions via targeted next-generation sequencing in cell-free DNA (cfDNA) isolated from cerebrospinal fluid (CSF) of AD patients homozygous for APOE4 (n=4) and sporadic AD (n=5) cases compared to age-matched control samples (n=5). Our analyses demonstrated that 6/11 of the tested DNA methylation signatures that had initially been identified in cortical neurons and brain tissue were also validated in cfDNA. The remainder of the tested regions either showed opposite trends (3/11) or did not result in any differences (2/11) between control and AD cases. Thus, this presents a direct approach allowing to test for these DNA methylation signatures in CSF-derived cfDNA, and bypasses the need to generate induced pluripotent stem cell-derived cortical neurons from patients.

neuroscience↗

bioRxiv2024

Loss of the Familial Dysautonomia gene Elp1 in cerebellar granule cell progenitors leads to ataxia in mice

Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have been described. ELP1 is highly expressed in the normal developing and adult cerebellum, but its role in cerebellum development is unknown. To investigate the cerebellar function of Elp1, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent 7 days after birth, when Elp1cKO animals also exhibited fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 within the developing cerebellum, and suggests that Elp1 loss in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.

neuroscience↗