Fiumara, F. | Search bioRxiv

bioRxiv2025

Prognostic and biological roles of Parkinson's disease genes in cancer

BackgroundIncreasing evidence suggests significant associations between Parkinson disease (PD) and cancer risks, with epidemiological studies revealing a complex relationship. PD patients exhibit lower risks of lung, genitourinary, and gastrointestinal cancers but higher risks of melanoma and brain cancers. Despite these observations, the underlying mechanisms between PD and cancers are poorly understood. ObjectivesWe aimed to identify molecular signatures that could provide insight into this complex connection by assessing the association of PD-related genes with patient survival and the cancer-specific co-expression networks they are involved in. MethodsTo explore this, we analyzed transcriptomic data from 18 cancer types in the TCGA dataset (n=6,088) and 16 cancer types in the DepMap dataset (n=682). We focused on seven genes causally implicated in PD (SNCA, PINK1, LRRK2, PRKN/PARK2, PARK7, GBA1, and ATP13A2) and conducted in silico analyses, to evaluate their associations with survival and correlation with genes, pathways and response to drugs in the context of cancer. ResultsOur findings revealed that the expression levels of the genes correlated with overall survival in a cancer-specific manner, often influenced by the TP53 genetic status. These genes were also associated with key cancer hallmarks such as genomic instability and cell proliferation. Additionally, novel associations were identified linking these genes to drug responses in a context-specific manner. ConclusionsThis study suggests that PD and cancer may be linked by biological pathways, sometimes associated with cancer hallmarks. These findings provide potential insights into druggable targets and the shared molecular mechanisms underlying PD and cancer.

bioinformatics↗

bioRxiv2024

The CDKL5 kinase undergoes liquid-liquid phase separation driven by a serine-rich C-terminal region and impaired by neurodevelopmental disease-related truncations

Mutations of the cyclin-dependent kinase-like 5 (CDKL5) gene, which encodes a serine/threonine protein kinase, can cause the CDKL5 deficiency disorder (CDD), a severe neurodevelopmental disease characterized by epileptic encephalopathy and neurocognitive impairment. The CDKL5 kinase consists of a catalytic N-terminal domain (NTD) and a less characterized C-terminal domain (CTD). Numerous disease-related mutations truncate CDKL5, leaving the NTD intact while variably shortening the CTD, which highlights the importance of the CTD for CDKL5 function. By systematically analyzing CDKL5 compositional features and evolutionary dynamics, we found that the CTD is a low-complexity region (LCR) highly enriched in serine residues and with a high propensity to undergo liquid-liquid phase separation (LLPS), a biophysical process of condensation controlling protein localization and function. Using a combination of super-resolution imaging, electron microscopy, and molecular and cellular approaches, including optogenetic LLPS induction, we discovered that CDKL5 undergoes LLPS, predominantly driven by its CTD, forming membraneless condensates in neuronal and non-neuronal cells. A CTD internal fragment (CTIF) plays a pivotal LLPS-promoting role, along with the distal portion of the protein. Indeed, two disease-related truncating mutations (S726X and R781X), eliding variable portions of the CTIF, significantly impair LLPS. This impairment is paralleled at the functional level by a reduction in the CDKL5-dependent phosphorylation of EB2, a known CDKL5 target. These findings demonstrate that CDKL5 undergoes LLPS, driven by a CTD region elided by most disease-related truncating mutations. Its loss--through the impairment of CDKL5 LLPS and functional activity--may play a key role in the molecular pathogenesis of CDD.

molecular biology↗