An archaeal compound as a driver of Parkinson’s disease pathogenesis

E-print/Working paper (2022)

Patients with Parkinson’s disease (PD) exhibit differences in their gut microbiomes compared to healthy individuals. Although differences have most commonly been described in the abundances of bacterial ... [more ▼]

Patients with Parkinson’s disease (PD) exhibit differences in their gut microbiomes compared to healthy individuals. Although differences have most commonly been described in the abundances of bacterial taxa, changes to viral and archaeal populations have also been observed. Mechanistic links between gut microbes and PD pathogenesis remain elusive but could involve molecules that promote α-synuclein aggregation. Here, we show that 2-hydroxypyridine (2-HP) represents a key molecule for the pathogenesis of PD. We observe significantly elevated 2-HP levels in faecal samples from patients with PD or its prodrome, idiopathic REM sleep behaviour disorder (iRBD), compared to healthy controls. 2-HP is correlated with the archaeal species Methanobrevibacter smithii and with genes involved in methane metabolism, and it is detectable in isolate cultures of M. smithii. We demonstrate that 2-HP is selectively toxic to transgenic α-synuclein overexpressing yeast and increases α-synuclein aggregation in a yeast model as well as in human induced pluripotent stem cell derived enteric neurons. It also exacerbates PD-related motor symptoms, α-synuclein aggregation, and striatal degeneration when injected intrastriatally in transgenic mice overexpressing human α-synuclein. Our results highlight the effect of an archaeal molecule in relation to the gut-brain axis, which is critical for the diagnosis, prognosis, and treatment of PD. [less ▲]

Neurodegeneration and neuroinflammation are linked, but independent of a-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease

in Glia (2022)

A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein (α-syn) is a presynaptic protein that, in PD, forms pathological inclusions. Other ... [more ▼]

A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein (α-syn) is a presynaptic protein that, in PD, forms pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α-syn particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used a model of spreading of α-syn induced by striatal injection of α-syn preformed fibrils into the mouse striatum to address this question. We performed quantitative analysis for α-syn inclusions, neurodegeneration, and microgliosis in different brain regions, and generated gene expression profiles of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α-syn inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. Using longitudinal gene expression profiling, we observed early gene expression changes, linked to neuroinflammation, that preceded neurodegeneration, indicating an active role of microglia in this process. Altered gene pathways overlapped with those typical of PD. Our observations indicate that α-syn inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that microglia, activated by diffusible, oligomeric α-syn, may play a key role in this process. Our findings uncover new features of α-syn induced pathologies, in particular microgliosis, and point to the necessity for a broader view of the process of α-syn spreading. [less ▲]

Quantitative trait locus mapping identifies a locus linked to striatal dopamine and points to collagen IV alpha-6 chain as a novel regulator of striatal axonal branching in mice

in Genes, Brain, and Behavior (2021)

Dopaminergic neurons (DA neurons) are controlled by multiple factors, many involved in neurological disease. Parkinson's disease motor symptoms are caused by the demise of nigral DA neurons, leading to ... [more ▼]

Dopaminergic neurons (DA neurons) are controlled by multiple factors, many involved in neurological disease. Parkinson's disease motor symptoms are caused by the demise of nigral DA neurons, leading to loss of striatal dopamine (DA). Here, we measured DA concentration in the dorsal striatum of 32 members of Collaborative Cross (CC) family and their eight founder strains. Striatal DA varied greatly in founders, and differences were highly heritable in the inbred CC progeny. We identified a locus, containing 164 genes, linked to DA concentration in the dorsal striatum on chromosome X. We used RNAseq profiling of the ventral midbrain of two founders with substantial difference in striatal DA–C56BL/6 J and A/J—to highlight potential protein-coding candidates modulating this trait. Among the five differentially expressed genes within the locus, we found that the gene coding for the collagen IV alpha 6 chain (Col4a6) was expressed nine times less in A/J than in C57BL/6J. Using single cell RNA-seq data from developing human midbrain, we found that COL4A6 is highly expressed in radial glia-like cells and neuronal progenitors, indicating a role in neuronal development. Collagen IV alpha-6 chain (COL4A6) controls axogenesis in simple model organisms. Consistent with these findings, A/J mice had less striatal axonal branching than C57BL/6J mice. We tentatively conclude that DA concentration and axonal branching in dorsal striatum are modulated by COL4A6, possibly during development. Our study shows that genetic mapping based on an easily measured Central Nervous System (CNS) trait, using the CC population, combined with follow-up observations, can parse heritability of such a trait, and nominate novel functions for commonly expressed proteins. [less ▲]

Gender-specific expression of ubiquitin-specific peptidase 9 modulates tau expression and phosphorylation: possible implications for tauopathies

in Molecular Neurobiology (2017), 54(10), 79797993

Public transcriptomics studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal ... [more ▼]

Public transcriptomics studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal disorders. Here we apply a transcriptome-wide analysis to discover genes with gender-specific expression and significant alterations in public post mortem brain tissue from Alzheimer’s disease (AD) patients compared to controls. We identify the sex-linked ubiquitin specific peptidase 9 (USP9) as an outstanding candidate gene with highly significant expression differences between the genders and male-specific under-expression in AD. Since previous studies have shown that USP9 can modulate the phosphorylation of the AD-associated protein MAPT, we investigate functional associations between USP9 and MAPT in further detail. After observing a high positive correlation between the expression of USP9 and MAPT in the public transcriptomics data, we show that USP9 knockdown results in significantly decreased MAPT expression in a DU145 cell culture model and a concentration-dependent decrease for the MAPT orthologs mapta and maptb in a zebrafish model. From the analysis of microarray and qRT-PCR experiments for the knockdown in DU145 cells and prior knowledge from the literature, we derive a data-congruent model for a USP9-dependent regulatory mechanism modulating MAPT expression via BACH1 and SMAD4. Overall, the analyses suggest USP9 may contribute to molecular gender differences observed in tauopathies and provide a new target for intervention strategies to modulate MAPT expression. [less ▲]

Exploring therapeutic viability of a non-dopaminergic target for Parkinson’s disease

in Movement Disorders (2016), 31(2), 630

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit.

in Neurobiology of Aging (2012), 33(6), 1123-17-1123-29

Soluble beta-amyloid (Aβ) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that Aβ ... [more ▼]

Soluble beta-amyloid (Aβ) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that Aβ oligomers activate cytosolic phospholipase A2 (cPLA2), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of Aβ oligomers in wild type mice. We further demonstrated that the Aβ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA2−/− mice. Interestingly, expression of the Aβ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA2−/− mice, but the relationship with the resistance of these mice to the Aβ oligomer toxicity requires further investigation. These results therefore show that cPLA2 plays a key role in the Aβ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease. Keywords Alzheimer's disease; Cytosolic phospholipase A2; Soluble beta-amyloid oligomers; Memory; Apoptosis; Synaptotoxicity; Amyloid precursor protein [less ▲]

The essential role of lipids in Alzheimer’s disease

in Biochimie (2009), 6

In the absence of efficient diagnostic and therapeutic tools, Alzheimer’s disease (AD) is a major public health concern due to longer life expectancy in the Western countries. Although the precise cause of ... [more ▼]

In the absence of efficient diagnostic and therapeutic tools, Alzheimer’s disease (AD) is a major public health concern due to longer life expectancy in the Western countries. Although the precise cause of AD is still unknown, soluble b-amyloid (Ab) oligomers are considered the proximate effectors of the synaptic injury and neuronal death occurring in the early stages of AD. Ab oligomers may directly interact with the synaptic membrane, leading to impairment of synaptic functions and subsequent signalling pathways triggering neurodegeneration. Therefore, membrane structure and lipid status should be considered determinant factors in Ab-oligomer-induced synaptic and cell injuries, and therefore AD progression. Numerous epidemiological studies have highlighted close relationships between AD inci- dence and dietary patterns. Among the nutritional factors involved, lipids significantly influence AD pathogenesis. It is likely that maintenance of adequate membrane lipid content could prevent the production of Ab peptide as well as its deleterious effects upon its interaction with synaptic membrane, thereby protecting neurons from Ab-induced neurodegeneration. As major constituents of neuronal lipids, n-3 polyunsaturated fatty acids are of particular interest in the prevention of AD valuable diet ingredients whose neuroprotective properties could be essential for designing preventive nutrition- based strategies. In this review, we discuss the functional relevance of neuronal membrane features with respect to susceptibility to Ab oligomers and AD pathogenesis, as well as the prospective capacities of lipids to prevent or to delay the disease. [less ▲]