Shvachiy, L. | Search bioRxiv

bioRxiv2024

Lead as a toxic environmental toxicant in models of synucleinopathies

Lead, a toxic heavy metal, is prevalent in various industrial applications, contributing to environmental contamination and significant health concerns. Lead affects various body systems, especially the brain, causing long-lasting cognitive and behavioral changes. While most studies have focused on continuous lead exposure, intermittent exposure, such as that caused by migration or relocations, has received less attention. Importantly, lead exposure intensifies the severity of Parkinsons disease (PD) and dementia with Lewy bodies, diseases involving the accumulation of alpha-synuclein (aSyn) in the brain and in the gut. Although, the precise mechanisms underlying these observations remain unclear, oxidative stress and mitochondrial dysfunction likely play a role. Here, we investigated how two different profiles of lead exposure - continuous and intermittent - affect models of synucleinopathies. We found that lead exposure enhances the formation of aSyn inclusions, resulting in an increase in both their number and size in cell models. In addition, we found that animals injected with aSyn pre-formed fibrils display serine 129-phosphorylated aSyn inclusions and a reduction in astrocytes in the substantia nigra. These animals also display neuronal damage and alterations in locomotor activity, exploratory behavior, anxiety, memory impairments and hypertension. Our results suggest a mechanistic link between environmental lead exposure and the onset and progression of diseases associated with aSyn pathology. Understanding the molecular and cellular interactions between lead and aSyn is crucial for shaping public health policies and may provide novel insight into strategies for mitigating the impact of environmental toxins on neurodegenerative processes involved in Parkinsons disease and related synucleinopathies. Key points summaryO_LILead exposure increases the number and size of alpha-synuclein (aSyn) inclusions in cell models.[~] C_LIO_LIAnimals exposed to aSyn fibrils and lead show increased phosphorylation of aSyn, neuronal damage and reduced astrogliosis in the substantia nigra. C_LIO_LILead-exposed animals exhibit impaired locomotion, anxiety, memory deficits, hypertension and chemoreceptor reflex hypersensitivity. C_LIO_LIThe study suggests a mechanistic link between environmental lead exposure and the progression of diseases involving aSyn pathology, such as Parkinsons disease. C_LI

physiology↗

bioRxiv2021

Glycation modulates glutamatergic signalling and exacerbates Parkinson's disease-like phenotypes

Alpha-synuclein (aSyn) is assumed to be a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinsons disease and, one common molecular alteration among these disorders is an age-associated increase in protein glycation. Thus, we hypothesized that glycation-induced dysfunction of neuronal pathways might be an underlying molecular cause of synucleinopathies. Here, we evaluated if increased brain glycation modulated motor and/or non-motor phenotypes in a mouse model of synucleinopathies. In addition, we dissected the specific impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain, and unveiled the major molecular pathways altered. Age-matched (16 weeks old) male aSyn transgenic (Thy1-aSyn) or WT mice received a single dose of MGO or vehicle via intracerebroventricular (ICV) injection. Behavioural phenotypes were analysed 4 weeks post-treatment, and, at the end of the tests, biochemical and histological studies were conducted on brain tissue. We found that glycation potentiates motor dysfunction, assessed by vertical pole, rotarod and hindlimb clasping tests in Thy1-aSyn mice. In addition, it induces cognitive impairment (Y maze test), olfactory disturbances (block test), and colonic dysfunction. These behavioural changes were accompanied by the accumulation of aSyn in the midbrain, striatum, and prefrontal cortex, and by an overall increase in glycation in the midbrain and cerebellum. Furthermore, MGO induced neuronal and dopaminergic cell loss in the midbrain of Thy1-aSyn mice. Quantitative proteomic analysis revealed that, in Thy1-aSyn mice, MGO mainly impacts on glutamatergic proteins in the midbrain, but not in the prefrontal cortex, where it mainly affects the electron transport chain. Among the altered proteins in the midbrain, we found an upregulation of N-Methyl-D-Aspartate (NMDA) and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors levels, glutaminase, vesicle glutamate transporter (VGLUT), and the excitatory amino acid transporter (EAAT1), suggesting potentiation of glutamatergic signalling. Overall, we demonstrated that MGO-induced glycation accelerates Parkinsonian-like sensorimotor and cognitive alterations. The increase in glutamatergic-related proteins in the midbrain may represent a compensatory mechanism to the MGO-induced dopaminergic neurodegeneration. Our study sheds light into the enhanced vulnerability of the midbrain in Parkinsons disease-related synaptic dysfunction that, ultimately leads to cell loss, and provides molecular insight into the observation that glycation suppressors and anti-glutamatergic drugs hold promise as disease-modifying therapies for synucleinopathies.

neuroscience↗