Biology subjects

Novikov, V.

Publications and source records attributed to Novikov, V..

3 recordsLinked to original sources

bioRxiv2026

Phosphorylated -Synuclein shapes changes in brain structure, task-related activity and functional connectivity in M83 mice

Phosphorylated -synuclein at S129 (pS129) is the predominant form of -synuclein in the aggregates known as Lewy bodies (LB) and Lewy neurites (LN), the pathological hallmarks of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), collectively known as synucleinopathies. The toxic nature of these inclusions remains contentious. To improve our understanding of these aggregates and their role in the structural and functional changes observed in synucleinopathies, we combined non-invasive structural and functional MRI in awake head-fixed M83 mice with whole-brain light-sheet fluorescence microscopy (LSFM) in the same animals following a unilateral injection of either human preformed fibrils of -synuclein (PFF) or PBS into the dorsal striatum. We developed a multimodal framework integrating the non-invasive, mesoscopic nature of MRI with the cellular-level details of LSFM to further our understanding of the underlying pathology of synucleinopathies. Using this framework, we show that four months after injection, animals injected with PFFs showed ubiquitous spread of pS129 pathology throughout the whole brain and spinal cord consistent with anatomical connectivity from the seeding region, with some structures such as the midbrain more susceptible to pS129 accumulation. Compared to controls, PFF-injected animals showed widespread atrophy as well as a decrease in functional connectivity, while evoked activity in the somatosensory/somatomotor areas in response to spontaneous paw movements showed significant hypoactivation. These cellular, structural and functional changes were significantly associated with the proportion of pS129 accumulation determined in the same animals. Our results demonstrate the deleterious effects of pS129 accumulation and argue in favor of a toxic role played by these aggregates.

neuroscience↗

bioRxiv2024

Sex-focused analyses of M83 A53T hemizygous mouse model with recombinant human alpha-synuclein preformed fibril injection identifies female resilience to disease progression: A combined magnetic resonance imaging and behavioural study.

Alpha-synuclein (aSyn) pathology has been extensively studied in mouse models harbouring human mutations. In spite of the known sex differences in age of onset, prevalence and disease presentation in human synucleinopathies, the impact of sex on aSyn propagation has received very little attention. To address this need, we examined sex differences in whole brain signatures of neurodegeneration due to aSyn toxicity in the M83 mouse model using longitudinal magnetic resonance imaging (MRI; T1-weighted; 100 m3 isotropic voxel; acquired -7, 30, 90 and 120 days post-injection [dpi]; n[≥]8 mice/group/sex/time point). To initiate aSyn spreading, M83 mice were inoculated with recombinant human aSyn preformed fibrils (Hu-PFF) or phosphate buffered saline (PBS) injected in the right dorsal striatum. We observed more aggressive neurodegenerative profiles over time for male M83 Hu-PFF-injected mice when examining voxel-wise trajectories. However, at 90 dpi, we observed widespread patterns of neurodegeneration in the female Hu-PFF-injected mice. These differences were not accompanied with any differences in motor symptom onset between the male and female Hu-PFF-injected mice. However, male Hu-PFF-injected mice reached their humane endpoint sooner. These findings suggest that post-motor symptom onset, even though more accelerated disease trajectories were observed for male Hu-PFF-injected mice, neurodegeneration may appear sooner in female Hu-PFF-injected mice (prior to motor symptomatology). These findings suggest that sex-specific synucleinopathy phenotypes urgently need to be considered to improve our understanding of neuroprotective and neurodegenerative mechanisms.

neuroscience↗

bioRxiv2022

Presymptomatic neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy

There is significant evidence suggesting aggregated misfolded alpha-synuclein, a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinsons disease (PD) and other synucleinopathies. Animal models are essential for understanding and developing treatments for these diseases. However, despite modelling human pathology, most endpoints studied in mice do not translate to humans. Furthermore, the progression by which alpha-synuclein misfolding affects human-relevant measures such as brain volume and underlying subtle, high-level cognitive deficits is poorly understood. Here we used a mouse model of synucleinopathy; hemizygous M83 human A53T alpha-synuclein transgenic mice inoculated with recombinant human alpha-synuclein preformed fibrils (PFF) injected in the right striatum to initiate alpha-synuclein misfolding and aggregation. We examined alpha-synuclein-induced atrophy at 90 days post-injection using ex vivo magnetic resonance imaging as well as high-level cognition and motor function, as biomarkers of alpha-synuclein toxicity. We observed widespread atrophy in bilateral regions that project to or receive input from the injection site, highlighting a network of regions that are consistent with structural changes observed in humans with PD. Moreover, we detected early deficits in reversal learning with touchscreen testing in PFF-injected mice prior to motor dysfunction, consistent with the pathology observed in cortical-striatal and thalamic loops. We show, using translational approaches in mice, that progression of prion-like spreading of alpha-synuclein causes selective atrophy via connected brain regions leading to high-level cognitive deficits. We propose that precise imaging and cognitive biomarkers can provide a more direct and human-relevant measurement of alpha-synuclein-induced toxicity in pre-clinical testing. Significance StatementThe work described in this manuscript showcases the utility of state-of-the-art methodologies (magnetic resonance imaging and touchscreen behavioural tasks) to examine endophenotypes, both in terms of symptomatology and neuroanatomy, of alpha-synuclein propagation in a mouse model of synucleinopathy. Our work further validates the M83-Hu-PFF mouse model of synucleinopathy-associated pathogenesis of neurodegenerative diseases while highlighting precise imaging and cognitive biomarkers of protein misfolding toxicity. Specifically, we identified rapid and translational biomarkers that can serve as a proxy for the direct examination of cellular levels for pathology. We anticipate that these biomarkers can measure progression of toxicity, specifically in the early phases, and may be more reliable than end stage pathology and more useful as endpoints in the examination of novel therapeutics.

neuroscience↗