Impact of genetic deficiency in the synthesis of brain-specific gangliosides and glycoproteins mediated by the ST3GAL3 and ST3GAL5 genes on the neuropathology

Background: Neurons and glia carry diverse glycolipids and glycoproteins, regulating their  interactions with cellular environment (Yoo et al.,2015). Sialic acids are playing a key role in these processes (Svennerholm,1994). Sialoglycan biosynthesis is mediated via glycosyltransferases, where glycoprotein/ganglioside sialyltransferase ST3GAL3 and ganglioside-specific sialyltransferase ST3GAL5 are critically important. Human mutations in genes St3gal3 and St3gal5 result in seizures, developmental delay, intellectual disability and increase a risk of neurodevelopmental disorders, including attention-deficit/hyperactivity disorder(ADHD) (Demontis et al.,2019;Hall et al.,2020;Klein et al.,2020;Rovira et al.,2020).

The mechanisms of neuropathology resulting from ST3GAL3 and ST3GAL5 dysfunction and the role of environmental factors in relation to these abnormalities are unclear, while roles of neuroinflammation (Dukhinova et al.,2018) and dysmyelination (Lesch,2019) were shown. Mice lacking St3gal5 demonstrate motor deficits, anxiety, aberrant social and cognitive behaviours, overexpression of pro-inflammatory cytokines and their dysregulation after challenges (Dukhinova et al.,2018). On another hand, various environmental factors increase a risk of neurodevelopmental pathologies/ADHD via pro-inflammatory changes, and interact with genetic mechanisms (Demontis et al.,2019). Infections and neuroinflammatory processes resulting from nutritional obesity and diabetes, can be such factors (Anand et al.,2017;Cortese,2019).

Given high medical and social need in understanding gene/environment factors underling neuropsychiatric pathologies, it is of high importance to study the role of ST3GAL3 and ST3GAL5 deficiency in this context. Particularly, this might concern (1)hall-marks of ADHD and neurodevelopmental conditions revealed in human studies; roles of (2)systemic inflammation and (3)dietary-induced metabolic conditions in the development of neuropathologies related to these genes;  (4)the effectiveness of the use nutrients such as omega-3 fatty acids and anti-inflammatory anti-oxidant derivatives of vitamin B1.

Methods: We will address cellular, molecular and behavioral phenotypes of St3gal3- and St3gal5-null mutant mice, uniquely available via Moscow, LPN, under normal conditions, dietary challenge and the use of anti-inflammatory/anti-oxidant nutrients. During the 1styear, mice will be studied for myelination and neuroinflammatory markers, motor functions, emotional, social and cognitive behaviours, also after the administration of drugs used during ADHD. A selection of molecular hallmarks of ADHD will be based on clinical studies of a Prof.Walitza group (Demontis et al.,2019;Grünblatt et al.,2019b,2019a,2013;Walitza et al., 2007,2005) and shall be performed using their unique the Bio-Plex assay analysis platform in Zürich.

During the 2ndyear, the role of environmental factors and nutrients changing oxidative stress and neuroinflammation in the development of ADHD-like pathology will be studied in both lines.  Juvenile St3gal3- and St3gal5 null mutants will be housed on high-fat/carbohydrate ‘Western’ diet inducing oxidative stress, neuroinflammation and ADHD-like-syndrome (Strekalova et al.,2016,2015;Veniaminova et al.,2020), or challenged with LPS. Chronic administration of anti-inflammatory thiamine(vitamin B1) compounds (Gorlova et al.,2019;Pavlov et al.,2020) and omega-3 fatty acids (Emery et al.,2020;Häberling et al.,2019) will be used also.

Anticipated results: Joint efforts of Moscow LPN providing unique work on mutant mice and Translational Molecular Psychiatry Laboratory in Zürich, offering specialized molecular techniques and clinic-based approach will let to determine new ADHD-related mechanisms of genetic inactivation of St3gal3 and St3gal5 and the impact of systemic inflammation, Western diet and anti-oxidant/anti-inflammatory nutrients under these conditions.

Participants:

University of Zurich

I.M. Sechenov First Moscow State Medical University