Biology subjects

Litvan, I.

Publications and source records attributed to Litvan, I..

10 recordsLinked to original sources

bioRxiv2025

Differential memory enrichment of cytotoxic CD4 T cells in Parkinson's disease patients reactive to α-synuclein

Parkinsons disease (PD) is a complex neurodegenerative disease with a largely unknown etiology. Although the loss of dopaminergic neurons in the substantia nigra pars compacta is the pathological hallmark of PD, neuroinflammation also plays a fundamental role in PD pathology. We have previously reported that PD patients have increased frequencies of T cell reactive to peptides from -synuclein (-syn). However, not all PD participants respond to -syn. Furthermore, we have previously found that CD4 T cells from PD participants responding to -syn (PD_R) are transcriptionally distinct from PD participants not responding to -syn (PD_NR). To gain further insight into the pathology of PD_R participants, we investigated surface protein expression of 11 proteins whose genes had previously been found to be differentially expressed when comparing PD_R and healthy control participants not responding to -syn (HC_NR). We found that Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) was expressed on a significantly higher proportion of CD4 effector memory T cells (TEM) in PD_R compared to HC_NR. Single-cell RNA sequencing analysis of cells expressing or not expressing CELSR2 revealed that PD_R participants have elevated frequencies of activated TEM subsets and an almost complete loss of cytotoxic TEM cells. Flow cytometry analyses confirmed that Granulysin+ CD4 cytotoxic TEM cells are reduced in PD_R. Taken together, these results provide further insight into the perturbation of T cell subsets in PD_R, and highlights the need for further investigation into the role of Granulysin+ CD4 cytotoxic TEM in PD pathology.

neuroscience↗

bioRxiv2025

T cell responses towards PINK1 and α-synuclein are elevated in prodromal Parkinson's disease

A role of the immune system in Parkinsons disease (PD) progression has long been suspected due to the increased frequency of activated glial cells and infiltrating T cells into the substantia nigra. It was previously reported that PD donors have increased T cell responses towards PINK1 and -synuclein (-syn), two Lewy body-associated proteins. Further, T cell reactivity towards -syn was highest closer to disease onset, highlighting that autoreactive T cells might play a role in PD pathogenesis. However, whether T cell autoreactivity is present during prodromal PD is unknown. Here, we investigated T cell responses towards PINK1 and -syn in donors at high risk of developing PD (i.e. prodromal PD: genetic risk, hyposmia, and or REM sleep behavior disorder), in comparison to PD and healthy control donors. T cell reactivity to these two autoantigens was detected in prodromal PD at levels comparable to those detected in individuals with clinically diagnosed PD. Aligned with the increased incidence of PD in males, we found that males with PD, but not females, had elevated T cell reactivity compared to healthy controls. However, among prodromal PD donors, males and females had elevated T cell responses. These differing trends in reactivity highlights the need for further studies of the impact of biological sex on neuroinflammation and PD progression.

neuroscience↗

bioRxiv2024

Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia

INTRODUCTIONSex differences are apparent in neurodegenerative diseases, but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODSParticipants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to six years. Linear mixed-effects models investigated how sex and disease stage associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTSWhile sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that attenuated in symptomatic participants. DISCUSSIONIn genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations.

neuroscience↗

bioRxiv2024

Chromogranin A Deficiency Attenuates Tauopathy by Altering Epinephrine Alpha-Adrenergic Receptor Signaling

Our previous studies have indicated that insulin resistance, hyperglycemia, and hypertension in aged wild-type (WT) mice can be reversed in mice lacking chromogranin-A (CgA-KO mice). These health conditions are associated with a higher risk of Alzheimers disease (AD). CgA, a neuroendocrine secretory protein has been detected in protein aggregates in the brains of AD patients. Here, we determined the role of CgA in tauopathies, including AD (secondary tauopathy) and corticobasal degeneration (CBD, primary tauopathy). We found elevated levels of CgA in both AD and CBD brains, which were positively correlated with increased phosphorylated tau in the frontal cortex. Furthermore, CgA ablation in a human P301S tau (hTau) transgenic mice (CgA-KO/hTau) exhibited reduced tau aggregation, resistance to tau spreading, and an extended lifespan, coupled with improved cognitive function. Transcriptomic analysis of mice cortices highlighted altered levels of alpha-adrenergic receptors (Adra) in hTau mice compared to WT mice, akin to AD patients. Since CgA regulates the release of the Adra ligands epinephrine (EPI) and norepinephrine (NE), we determined their levels and found elevated EPI levels in the cortices of hTau mice, AD and CBD patients. CgA-KO/hTau mice exhibited reversal of EPI levels in the cortex and the expression of several affected genes, including Adra1 and 2, nearly returning them to WT levels. Treatment of hippocampal slice cultures with EPI or an Adra1 agonist intensified, while an Adra1 antagonist inhibited, tau hyperphosphorylation and aggregation. These findings reveal a critical role of CgA in regulation of tau pathogenesis via the EPI-Adra signaling axis.

neuroscience↗

bioRxiv2024

PINK1 is a target of T cell responses in Parkinson's disease

Parkinsons disease (PD) is associated with autoimmune T cells that recognize the protein alpha-synuclein in a subset of individuals. Multiple neuroantigens are targets of autoinflammatory T cells in classical central nervous system autoimmune diseases such as multiple sclerosis (MS). Here, we explored whether additional autoantigenic targets of T cells in PD. We generated 15-mer peptide pools spanning several PD-related proteins implicated in PD pathology, including GBA, SOD1, PINK1, parkin, OGDH, and LRRK2. Cytokine production (IFN{gamma}, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. This approach identified unique epitopes and their HLA restriction from the mitochondrial-associated protein PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells. The T cell reactivity was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.

immunology↗

bioRxiv2022

Nicked tRNAs are stable reservoirs of tRNA halves in cells and biofluids

Nonvesicular extracellular RNAs (nv-exRNAs) constitute the majority of the extracellular RNAome, but little is known about their stability, function and potential use as disease biomarkers. Herein, we measured the stability of several naked RNAs when incubated in human serum, urine and cerebrospinal fluid (CSF). We identified extracellularly produced tRNA-derived small RNAs (tDRs) with half-lives of up to three hours in CSF. Contrary to widespread assumptions, these intrinsically stable small RNAs are full-length tRNAs containing broken phosphodiester bonds (i.e., nicked tRNAs). Standard molecular biology protocols, including phenol-based RNA extraction and heat, induce the artifactual denaturation of nicked tRNAs and the consequent in vitro production of tDRs. Broken bonds are roadblocks for reverse transcriptases, preventing amplification and/or sequencing of nicked tRNAs in their native state. To solve this, we performed enzymatic repair of nicked tRNAs purified under native conditions, harnessing the intrinsic activity of phage and bacterial tRNA repair systems. Enzymatic repair regenerated an RNase R-resistant tRNA-sized band in northern blot and enabled RT-PCR amplification of full-length tRNAs. We also separated nicked tRNAs from tDRs by chromatographic methods under native conditions, identifying nicked tRNAs inside stressed cells and in vesicle-depleted human biofluids. Dissociation of nicked tRNAs produces single-stranded tDRs that can be spontaneously taken up by human epithelial cells, positioning stable nv-exRNAs as potentially relevant players in intercellular communication pathways.

molecular biology↗

bioRxiv2022

Unaltered T cell responses to common antigens in individuals with Parkinson's disease

Background and ObjectivesParkinsons disease (PD) is associated with a heightened inflammatory state, including activated T cells. However, it is unclear whether these PD T cell responses are antigen specific or more indicative of generalized hyperresponsiveness. Our objective was to measure and compare antigen-specific T cell responses directed towards antigens derived from commonly encountered human pathogens/vaccines in patients with PD and age-matched healthy controls (HC). MethodsPeripheral blood mononuclear cells (PBMCs) from 20 PD patients and 19 age-matched HCs were screened. Antigen specific T cell responses were measured by flow cytometry using a combination of the activation induced marker (AIM) assay and intracellular cytokine staining. ResultsHere we show that both PD patients and HCs show similar T cell activation levels to several antigens derived from commonly encountered human pathogens/vaccines in the general population. Similarly, we also observed no difference between HC and PD in the levels of CD4 and CD8 T cell derived cytokines produced in response to any of the common antigens tested. These antigens encompassed both viral (coronavirus, rhinovirus, respiratory syncytial virus, influenza, cytomegalovirus) and bacterial (pertussis, tetanus) targets. ConclusionsThese results suggest the T cell dysfunction observed in PD may not extend itself to abnormal responses to commonly encountered or vaccine-target antigens. Our study supports the notion that the targets of inflammatory T cell responses in PD may be more directed towards autoantigens like -synuclein (-syn) rather than common foreign antigens.

immunology↗

bioRxiv2021

Transcriptional analysis of peripheral memory T cells reveals Parkinson's disease-specific gene signatures

Parkinsons disease (PD) is a multi-stage neurodegenerative disorder with largely unknown etiology. Recent findings have identified PD-associated autoimmune features including roles for T cells. To further characterize the role of T cells in PD, we performed RNA sequencing on PBMC and peripheral CD4 and CD8 memory T cell subsets derived from PD patients and age-matched healthy controls. When the groups were stratified by their T cell responsiveness to alpha-synuclein (-syn) as a proxy for ongoing inflammatory autoimmune response, the study revealed a broad differential gene expression profile in memory T cell subsets and a specific PD associated gene signature. We identified a significant enrichment of transcriptomic signatures previously associated with PD, including for oxidative stress, phosphorylation, autophagy of mitochondria, cholesterol metabolism and inflammation, and the chemokine signaling proteins CX3CR1, CCR5 and CCR1. In addition, we identified genes in these peripheral cells that have previously been shown to be involved in PD pathogenesis and expressed in neurons, such as LRRK2, LAMP3, and aquaporin. Together, these findings suggest that features of circulating T cells with -syn-specific responses in PD patients provide insights into the interactive processes that occur during PD pathogenesis and suggest potential intervention targets.

immunology↗

bioRxiv2019

Occupation and Parkinson disease in Women's Health Initiative Observational Study

IntroductionThere is a lack of consistency in associations between workplace factors and risk of Parkinson disease (PD), and paucity of such data on women. We took a classic occupational epidemiology approach that assesses associations with occupational groups in order to derive insights about potential occupation-specific exposures that may be causal. MethodsThe Womens Health Initiative (WHI-OS) is a prospective cohort that enrolled 91,627 postmenopausal women, 50 to 79 years of age from 10/01/93 to 12/31/98, at 40 clinical centers across the US with average follow-up of 11 years, who reported up to three paid jobs held the longest since age 18; these jobs were coded and duration of employment calculated. We defined the case by self-report of doctor-diagnosed PD (at baseline or follow-up), death attributed to PD, or medication consistent with PD. ResultsAmong 2,590 cases, we report evidence of excess risk among "counselors, social workers, and other community and social service specialists". There was a suggestion of increase in risk among post-secondary teachers, and "building and grounds cleaning and maintenance". There was also evidence of deficit in risk among women who worked in sales. Results with ever-employed and duration were similar, except for evidence of excess of risk among "health technologists and technicians" with more than 20 years of employment. Longer duration of life on a farm was associated with higher risk. ConclusionOur findings paint a largely reassuring picture of occupational risks for PD among US women, especially for trades largely unaffected by recent technological advances.

epidemiology↗

bioRxiv2019

Neuropathological validation of the MDS-PSP criteria with PSP and other frontotemporal lobar degeneration

BackgroundProgressive supranuclear palsy (PSP) is clinically heterogeneous. Clinical diagnostic criteria were revised in 2017, to increase sensitivity and operationalize the diagnosis of PSP Richardsons syndrome (PSP-RS) and \"variant\" syndromes (vPSP).\n\nObjectivesTo determine the (1) sensitivity and specificity of the 1996 NINDS-SPSP and 2017 MDS-PSP criteria; (2) false positive rates in frontotemporal dementia with frontotemporal lobar degeneration (FTLD); and (3) clinical evolution of variant PSP syndromes (vPSP).\n\nMethodsRetrospective multicenter review of 108 neuropathologically-confirmed PSP patients and 81 patients with other forms of FTLD: 38 behavioral variant frontotemporal dementia (bvFTD), 14 non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), and 29 corticobasal degeneration (CBD), Sensitivity and specificity of the MDS-PSP criteria were compared to the NINDS-SPSP criteria at baseline. In a subset of cases, the timing and frequency of clinical features were compared across groups over six years.\n\nResultsSensitivity for recognition of probable and possible PSP pathology was higher by MDS-PSP criteria (72.2-100%) than NINDS-SPSP criteria (48.1-61.1%). Specificity was higher by NINDS-SPSP criteria (97.5-100%) than MDS-PSP criteria (53.1-95.1%). False positives by MDS-PSP criteria were few for bvFTD (10.5-18.4%) but common for CBD and nfvPPA (fulfilling \"suggestive of PSP). Most vPSP cases developed PSP-RS-like features within six years, including falls and supranuclear gaze palsy, distinguishing frontal presentations of PSP from bvFTD, and speech/language presentations of PSP from nfvPPA.\n\nConclusionsThe 2017 MDS-PSP criteria successfully identify PSP, including variant phenotypes. This independent validation of the revised clinical diagnostic criteria strengthens the case for novel therapeutic strategies against PSP to include variant presentations.

neuroscience↗