Research News

Abstract: Parkinson’s disease and inflammatory bowel disease have been increasingly associated, implying shared pathophysiology. To explore biological explanations for the reported connection, we leveraged summary statistics of updated genome-wide association studies and characterized the genetic overlap between the two diseases. Aggregated genetic association data were available for 37 688 cases versus 981 372 controls for Parkinson’s disease and 25 042 cases versus 34 915 controls for inflammatory bowel disease. Genetic correlation was estimated with the high-definition likelihood method. Genetic variants with joint association to both diseases were identified by conditional false discovery rate framework and further annotated to reveal shared loci, genes, and enriched pathways. For both Crohn’s disease and ulcerative colitis, the two main subtypes of inflammatory bowel disease, we detected weak but statistically significant genetic correlations with Parkinson’s disease (Crohn’s disease: r_g = 0.06, P = 0.01; ulcerative colitis: r_g = 0.06, P = 0.03). A total of 1290 variants in 27 independent genomic loci were detected to associate with Parkinson’s disease and Crohn’s disease at conjunctional false discovery rate under 0.01 and 1359 variants in 15 loci were pleiotropic to Parkinson’s disease and ulcerative colitis. Among the identified pleiotropic loci, 23 are novel and have never been associated with both phenotypes. A mixture of loci conferring either same or opposing genetic effects on two phenotypes was also observed. Positional and expression quantitative trait loci mapping prioritized 296 and 253 genes for Parkinson’s disease with Crohn’s disease and ulcerative colitis, respectively, among which only <10% are differentially expressed in both colon and substantia nigra. These genes were identified to overrepresent in pathways regulating gene expression and post-translational modification beyond several immune-related pathways enriched by major histocompatibility complex genes. In conclusion, we found robust evidence for a genetic link between Parkinson’s disease and inflammatory bowel disease. The identified genetic overlap is complex at the locus and gene levels, indicating the presence of both synergistic and antagonistic pleiotropy. At the functional level, our findings implied a role of immune-centered mechanisms in the reported gut-brain connection.

Xiaoying Kang, Alexander Ploner, Yunzhang Wang, Jonas F Ludvigsson, Dylan M Williams, Nancy L Pedersen, Karin Wirdefeldt, Genetic overlap between Parkinson’s disease and inflammatory bowel disease, Brain Communications, Volume 5, Issue 1, 2023, fcad002, https://doi.org/10.1093/braincomms/fcad002

https://academic.oup.com/braincomms/article/5/1/fcad002/6967738

Editor’s summary: The autoimmune disease multiple sclerosis (MS) is a highly heterogeneous disease with many different treatment options. However, it is not clear whether certain features of MS are associated with distinct immune signatures or would benefit from particular therapies. Here, Gross et al. used peripheral blood mononuclear cells and serum collected from two independent cohorts of patients with MS to identify three endophenotypes of the disease. These peripheral blood immune signatures distinguished patients with distinct clinical disease trajectories and efficacy of interferon-β treatment. These data suggest that peripheral blood analysis could be used to guide personalized treatment regimens for patients with MS.

Abstract:  One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection based on immunobiological principles is still not feasible. Using two independent multicentric longitudinal cohorts of patients with early multiple sclerosis (n = 309 discovery and n = 232 validation), we were able to identify three distinct peripheral blood immunological endophenotypes by a combination of high-dimensional flow cytometry and serum proteomics, followed by unsupervised clustering. Longitudinal clinical and paraclinical follow-up data collected for the cohorts revealed that these endophenotypes were associated with disease trajectories of inflammation versus early structural damage. Investigating the capacity of immunotherapies to normalize endophenotype-specific immune signatures revealed discrete effect sizes as illustrated by the limited effect of interferon-β on endophenotype 3–related immune signatures. Accordingly, patients who fell into endophenotype 3 subsequently treated with interferon-β exhibited higher disease progression and MRI activity over a 4-year follow-up compared with treatment with other therapies. We therefore propose that ascertaining a patient’s blood immune signature before immunomodulatory treatment initiation may facilitate prediction of clinical disease trajectories and enable personalized treatment decisions based on pathobiological principles.

Abstract:  

Aims: According to Braak’s hypothesis, it is plausible that Parkinson’s disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons.

Methods: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology.

Results: Our data support the existence of pathogenic α-syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS-based rat model of gut inflammation to demonstrate (i) the appearance of P-α-syn inclusions in both Auerbach’s and Meissner’s plexuses (gut), (ii) an increase in α-syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD.

Conclusion: These results strongly support the plausibility of Braak’s hypothesis and emphasise the significance of peripheral inflammation and the gut-brain axis in initiating α-syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.

Espinosa-Oliva AM, Ruiz R, Soto MS, Boza-Serrano A, Rodriguez-Perez AI, Roca-Ceballos MA, García-Revilla J, Santiago M, Serres S, Economopoulus V, Carvajal AE, Vázquez-Carretero MD, García-Miranda P, Klementieva O, Oliva-Martín MJ, Deierborg T, Rivas E, Sibson NR, Labandeira-García JL, Machado A, Peral MJ, Herrera AJ, Venero JL, de Pablos RM. Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain. Neuropathol Appl Neurobiol. 2024 Feb;50(1):e12962. doi: 10.1111/nan.12962. PMID: 38343067.

https://pubmed.ncbi.nlm.nih.gov/38343067/?dopt=Abstract

Abstract: The expanding field of precision gene editing using CRISPR/Cas9 has demonstrated its potential as a transformative technology in the treatment of various diseases. However, whether this genome-editing tool could be used to modify neural circuits in the central nervous system (CNS), which are implicated in complex behavioral traits, remains uncertain. In this study, we demonstrate the feasibility of noninvasive, intranasal delivery of adeno-associated virus serotype 9 (AAV9) vectors containing CRISPR/Cas9 cargo within the CNS resulting in modification of the HTR2A receptor gene. In vitro, exposure to primary mouse cortical neurons to AAV9 vectors targeting the HT2RAgene led to a concentration-dependent decrease in spontaneous electrical activity following multielectrode array (MEA) analysis. In vivo, at 5 weeks postintranasal delivery in mice, analysis of brain samples revealed single base pair deletions and nonsense mutations, leading to an 8.46-fold reduction in mRNA expression and a corresponding 68% decrease in the 5HT-2A receptor staining. Our findings also demonstrate a significant decrease in anxiety-like behavior in treated mice. This study constitutes the first successful demonstration of a noninvasive CRISPR/Cas9 delivery platform, capable of bypassing the blood-brain barrier and enabling modulation of neuronal 5HT-2A receptor pathways. The results of this study targeting the HTR2A gene provide a foundation for the development of innovative therapeutic strategies for a broad range of neurological disorders, including anxiety, depression, attentional deficits, and cognitive dysfunction.

Rohn TT, Radin D, Brandmeyer T, Linder BJ, Andriambeloson E, Wagner S, Kehler J, Vasileva A, Wang H, Mee JL, Fallon JH. Genetic modulation of the HTR2A gene reduces anxiety-related behavior in mice. PNAS Nexus. 2023 Jun 20;2(6):pgad170. doi: 10.1093/pnasnexus/pgad170. PMID: 37346271; PMCID: PMC10281383.

https://pubmed.ncbi.nlm.nih.gov/37346271/

Abstract: “Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.”

Ross, J.B., Myers, L.M., Noh, J.J. et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature (2024). https://doi.org/10.1038/s41586-024-07238-x

https://www.nature.com/articles/s41586-024-07238-x

Abstract:      Accumulating evidence suggests that the Epstein-Barr virus (EBV) plays a key role in the development of multiple sclerosis (MS). Additionally, depressive symptoms often precede the onset of MS. Given the role of the XBP1-sigma-1 receptor complex in the endoplasmic reticulum during EBV reactivation, the author proposes that fluvoxamine, an antidepressant with sigma-1 receptor agonism, could be a suitable therapeutic drug for MS.

Hashimoto K. Viewpoints Sigma-1 receptor agonist fluvoxamine for multiple sclerosis. Brain Behav Immun Health. 2024 Mar 13;37:100752. doi: 10.1016/j.bbih.2024.100752. PMID: 38524897; PMCID: PMC10957369.

https://pubmed.ncbi.nlm.nih.gov/38524897/

Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator-activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific Bdnf knockout (MBKO) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced β-oxidation, and dysregulated mitochondrial dynamics. Moreover, MBKO mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.

Chan WS, Ng CF, Pang BPS, Hang M, Tse MCL, Iu ECY, Ooi XC, Yang X, Kim JK, Lee CW, Chan CB. Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery. Sci Signal. 2024 Mar 19;17(828):eadh2783. doi: 10.1126/scisignal.adh2783. Epub 2024 Mar 19. PMID: 38502732.

https://pubmed.ncbi.nlm.nih.gov/38502732/

Abstract:

Introduction: The etiology of multiple sclerosis (MS) remains unknown. Pathogenesis likely relies on a complex interaction between multiple environmental, genetic, and behavioral risk factors. However, a growing body of literature supports the role of a preceding Epstein-Barr virus (EBV) infection in the majority of cases.

Areas covered: In this narrative review, we summarize the latest findings regarding the potential role of EBV as a predisposing event inducing new onset of MS. EBV interactions with the genetic background and other infectious agents such as human endogenous retrovirus are explored. Additional data regarding the role of EBV regarding the rate of mid- and long-term disease progression is also discussed. Lastly, the effect of currently approved disease-modifying therapies (DMT) for MS treatment on the EBV-based molecular mechanisms and the development of new EBV-specific therapies are further reviewed.

Expert opinion: Recent strong epidemiological findings support that EBV may be the primary inducing event in certain individuals that shortly thereafter develop MS. More studies are needed in order to better understand the significant variability in susceptibility based on environmental factors such as EBV exposure. Future investigations should focus on determining the specific EBV-related risk antigen(s) and phenotyping people with likely EBV-induced MS. Targeting EBV via several different avenues, including development of an EBV vaccine, may become the mainstay of MS treatment in the future.

Eckert S, Jakimovski D, Zivadinov R, Hicar M, Weinstock-Guttman B. How to and should we target EBV in MS? Expert Rev Clin Immunol. 2024 Mar 15:1-12. doi: 10.1080/1744666X.2024.2328739. Epub ahead of print. PMID: 38477887.

https://pubmed.ncbi.nlm.nih.gov/38477887/

Long-Term Autoimmune Inflammatory Rheumatic Outcomes of COVID-19

“Preliminary evidence suggests a possible higher incidence of diagnosis of autoimmune inflammatory rheumatic diseases (AIRDs) among patients with a history of COVID-19, but whether this association is specific to SARS-CoV-2 infection is unclear. This study compared the risk for AIRD in patients with a recent SARS-CoV-2 infection versus those with recent influenza infection and those with no infection….

Conclusion:

SARS-CoV-2 infection was associated with increased risk for incident AIRD compared with matched patients without SARS-CoV-2 infection or with influenza infection. The risk for incident AIRD was higher with greater severity of acute COVID-19.“

Kim MS et al., Long-Term Autoimmune Inflammatory Rheumatic Outcomes of CZoVID-19. A Binational Cohort Study. Annals of Internal Medicine (March 5, 2024) https://doi.org/10.7326/M23-1831

https://www.acpjournals.org/doi/10.7326/M23-1831

“…Search yielded in total 345 publications, 257 thereof with psychiatric topic, 72 on personality disorder or traits, 43 of which were in humans and epigenetic, 23 thereof were original studies. Lastly, 23 original publications fulfilled the intended search criteria and were included. Those are 13 studies on gene methylation pattern with aggressive, antisocial and impulsive traits, 9 with borderline personality disorder (BPD), and 2 with antisocial personality disorder (ASPD). The results of these studies showed significant associations of PD with methylation aberrances in system-wide genes and suggest evidence for epigenetic processes in the development of personality traits and personality disorders. Environmental factors, of which childhood trauma showed a high impact, interfered with many neurofunctional genes. Methylation alterations in ASPD and BPD repeatedly affected HTR2A, HTR3A, NR3C1, and MAOA genes. …”

Gescher DM, Kahl KG, Hillemacher T, Frieling H, Kuhn J, Frodl T. Epigenetics in Personality Disorders: Today’s Insights. Front Psychiatry. 2018 Nov 19;9:579. doi: 10.3389/fpsyt.2018.00579. PMID: 30510522; PMCID: PMC6252387.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252387/