Biology subjects

Malankhanova, T.

Publications and source records attributed to Malankhanova, T..

5 recordsLinked to original sources

bioRxiv2026

Rab12 is a regulator of mitophagy and mitochondrial homeostasis

Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.

cell biology↗

bioRxiv2025

Lysosomal swelling triggers LRRK2 activity

LRRK2 is implicated in lysosomal functions, but the physiological upstream cues that engage endogenous LRRK2 activity are incompletely defined. Here we show that lysosomal swelling serves as a selective and reversible trigger for LRRK2-mediated Rab phosphorylation, without requiring membrane damage. Acute inhibition of PIKfyve, but not the general disruption of phosphoinositide signaling, induces the robust accumulation of phosphorylated Rabs across endolysosomal membranes. Rescue of swelling through pharmacological restoration of lysosomal ionic imbalances from PIKfyve inhibition suppresses LRRK2 activation without restoring lysosomal function. Mechanical lysosomal swelling from indigestible osmolyte uptake causes a dose-dependent increase in LRRK2-mediated Rab phosphorylation on both swollen and non-swollen lysosomes. Together, these findings identify LRRK2 as a sensor of lysosomal volume and mechanical stress, not specifically membrane damage or PIKfyve inhibition. As lysosomal swelling is a shared pathological feature across LRRK2-linked diseases, these results reframe LRRK2 as part of an endolysosomal surveillance system responsive to lysosomal distension.

neuroscience↗

bioRxiv2025

Accumulation of LRRK2-associated phospho-Rab12 degenerative lysosomes in tauopathies

Parkinsons disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated tau and -synuclein deposits in post-mortem analysis. LRRK2 mutations increase the phosphorylation of Rab substrates including Rab12. Rab12 is expressed in neuronal and non-neuronal cells with localization to membranes in the endolysosomal compartment. Under lysosomal stress, LRRK2 interaction with Rab12 upregulates LRRK2 kinase activity. In this study, using a recently developed monoclonal antibody directed to the LRRK2-mediated phosphorylation site on Rab12 at amino acid Ser106 (pS106-Rab12), we test whether aberrant LRRK2 phosphorylation is associated with tau and/or -synuclein pathology across clinically distinct neurodegenerative diseases. Analysis of brain tissue lysates and immunohistochemistry of pathology-susceptible brain regions demonstrate that pS106-Rab12 levels are increased in Dementia with Lewy bodies (DLB), Alzheimers disease (AD), and PD, and in LRRK2 mutation carriers. In early pathological stages, phosphorylated Rab12 localizes to granulovacuolar degeneration bodies (GVBs), which are thought to be active lysosomal-like structures, in neurons. pS106-Rab12-positive GVBs accumulate with pathological tau across brain tissues in DLB, AD, and PD, and in LRRK2 mutation carriers. In a mouse model of tauopathy, pS106-Rab12 localizes to GVBs during early tau deposition in an age-dependent manner. While GVBs are largely absent in neurons with mature protein pathology, subsets of both tau and -synuclein inclusions appear to incorporate pS106-Rab12 at later pathological stages. Finally, pS106-Rab12 labels GVBs in neurons and shows widespread co-pathology with tau inclusions in primary tauopathies including Picks disease, progressive supranuclear palsy and corticobasal degeneration. These results implicate LRRK2 kinase activity and Rab phosphorylation in endolysosomal dysfunction in both tau and -synuclein-associated neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases

Short AbstractThe intricate process of -synuclein aggregation and fibrillization hold pivotal roles in Parkinsons disease (PD) and multiple system atrophy (MSA). While mouse -synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here we report the first atomic structure of mouse -synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse -synuclein fibrils display altered packing arrangements, reduced hydrophobicity, heightened fragmentation sensitivity, and evoke only weak immunological responses. Furthermore, mouse -synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized -synuclein mice. These findings provide new insights into the structural underpinnings of -synuclein pathogenicity and emphasize a need to reassess the role of mouse -synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.

neuroscience↗

bioRxiv2018

Generation and characterization of iPSCs from human embryonic dermal fibroblasts of a healthy donor from Siberian population

Technology of reprogramming of somatic cells to a pluripotent state allows generating induced pluripotent stem cells (iPSCs) and carrying out a broad range of studies. iPSCs can be obtained from patients suffering from inherited diseases to model the diseases and to study their pathological mechanisms at the molecular level after iPSC differentiation in relevant cell types. Another approach to model and study inherited diseases is using iPSCs from healthy donors and genome editing tools. The approach allows generating a panel of isogenic lines, which gives new opportunities in drug screening and toxicological testing. Moreover, iPSCs and their derivatives can be further used for substitutive cell therapy and transplantology.\n\nIn this study, we generated iPSCs from human embryonic fibroblasts using episomal vectors. The lines obtained expressed pluripotency markers, had a stable karyotype - 46:XY, and did not contain episome integrations into genome. The cell lines gave rise to derivatives of three germ layers during spontaneous differentiation in vitro and in vivo.

cell biology↗