Regional expression of genes mediating trans-synaptic alpha-synuclein transfer predicts regional atrophy in Parkinson disease

Dzyubachyk

Hilten

et al. 2020

Preprint

Cortical atrophy is a common manifestation in Parkinson's disease, particularly in later disease stages. Here, we investigated patterns of cortical thickness using T1-weighted anatomical MRI data of 149 Parkinson's disease patients and 369 controls. To elucidate the molecular underpinnings of cortical thickness changes in Parkinson's disease, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and neuroimaging features. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of Parkinson's disease. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in Parkinson's disease are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in Parkinson's disease and possibly influence motor and cognitive functions. Abbreviations: AHBA = Allen Human Brain Atlas; CT = cortical thickness; LED = levodopa equivalent dose; MDS-UPDRS = Movement Disorder Society-sponsored revision of the unified Parkinson's disease rating scale; MMSE = mini-mental state examination; PLS = partial least squares; SENS-PD = severity of non-dopaminergic symptoms in Parkinson's disease Running title: Gene expression and cortical thickness

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Transcriptomic signatures associated with regional cortical thickness changes in Parkinson’s disease

Dzyubachyk

Hilten

et al. 2020

Preprint

“…Spatial gene expression patterns in the human brain have been studied to unravel the pathogenic mechanisms underlying amyloid-β and tau pathology progression in Alzheimer’s disease, revealing proteins that co-aggregate with amyloid-β and tau, and protein homeostasis components 13,14 . Interestingly, by integrating Allen Human Brain Atlas (AHBA) gene expression data 15 with magnetic resonance imaging of PD patients, the regional expression pattern of MAPT and SNCA was associated with loss of functional connectivity in PD 16 , and regional expression of synaptic transfer genes was related to regional gray matter atrophy in PD 17 . This combined gene-MRI analysis illustrates the importance of local gene expression changes on functional brain networks.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Mahfouz

Ingrassia

et al. 2019

Preprint

25The molecular mechanisms underlying the caudal-to-rostral progression of Lewy body pathology in 26Parkinson's disease (PD) remain poorly understood. Here, we aimed to unravel transcriptomic signatures 27 across brain regions involved in Braak Lewy body stages in non-neurological controls and PD donors. 28Using human postmortem brain datasets of non-neurological adults from the Allen Human Brain Atlas, we 29 identified expression patterns related to PD progression, including genes found in PD genome-wide 30 associations studies: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, and SCARB2. We confirmed these 31 patterns in two datasets of non-neurological subjects (Genotype-Tissue Expression project and UK Brain 32 Expression Consortium) and found altered patterns in two datasets of PD patients. Additionally, co-33 expression analysis across vulnerable regions identified two modules associated with dopamine 34 synthesis, the motor and immune system, blood-oxygen transport, and contained microglial and 35 endothelial cell markers, respectively. Alterations in genes underlying these region-specific functions may 36 contribute to the selective regional vulnerability in PD brains. 37 38 3 Background 39 Parkinson's disease (PD) is characterized by a temporal caudal-rostral progression of Lewy body (LB) 40 pathology across a selected set of nuclei in the brain 1 . The distribution pattern of LB pathology is divided 41 into six Braak stages based on accumulation of the protein α-synucleinthe main component of LBs and 42 Lewy neuritesin the brainstem, limbic and neocortical regions 1 . Different hypotheses have been 43 brought forward to explain the evolving LB pathology across the brain, including: retrograde transport of 44 pathological α-synuclein via neuroanatomical networks, α-synuclein's prion-like behavior, and cell-or 45 region-autonomous factors 2,3 . Yet, the mechanisms underlying the selective vulnerability of brain regions 46 to LB pathology remains poorly understood, limiting the ability to diagnose and treat PD. 47 Multiplications of the SNCA gene encoding α-synuclein are relatively common in autosomal dominant PD 48and SNCA dosage has been linked to the severity of PD 4,5 . For other PD-associated variants, e.g. GBA 49and LRRK2, their role in progressive α-synuclein accumulation is less clear, although they have been 50 associated with mitochondrial (dys)function and/or protein degradation pathways [6][7][8] . On the other hand, 51 transcriptomic changes between PD and non-neurological controls of selected brain regions, e.g. the 52 substantia nigra, have identified several molecular mechanisms underlying PD pathology, including 53 synaptic vesicle endocytosis [9][10][11] . However, post-mortem human brain tissue of well-characterized PD 54 patients and controls is scarce, usually focuses on a select number of brain regions, and have a limited 55 coverage of patients with different Braak LB stages, resulting in low concordance of findings across 56 different studies 12 . 57Spatial gene expression patterns in the human ...

“…To identify the molecular mechanisms underlying changes in structural and functional networks in PD, imaging data has been integrated with brain wide expression atlases of the healthy brain (Hawrylycz et al 2015; Arnatkevičiūtė et al 2019). Regional brain atrophy in PD patients was found to be correlated with the expression of genes implicated in trans-synaptic alpha-synuclein transfer (Freeze et al 2018) and a loss of regional connectivity in PD patients was correlated with the regional expression of MAPT in the healthy brain (Rittman et al 2016). These studies show that combining imaging data in PD and gene expression from the healthy brain can shed light on the molecular mechanisms underlying the observed differences between PD and controls.…”

Section: Introductionmentioning

confidence: 99%

Cholinergic circuit genes in the healthy brain are differentially expressed in regions that exhibit gray matter loss in Parkinson’s disease

Dzyubachyk

et al. 2019

Preprint

Structural covariance networks are able to identify functionally organized brain regions by gray matter volume covariance. In Parkinson’s disease, the posterior cingulate network and anterior cingulate network showed decreased gray matter and therefore we examined the underlying molecular processes of these anatomical networks in the healthy brain. Whole brain transcriptomics from post-mortem samples from healthy adults, revealed upregulation of genes associated with serotonin, GPCR, GABA, glutamate, and RAS signaling pathways in these PD-related regions. Our results also suggest involvement of the cholinergic circuit, in which genes NPPA, SOSTDC1, and TYRP1 may play a protective role. Furthermore, both networks were associated with memory and neuropsychiatric disorders that overlap with Parkinson’s disease symptoms. The identified genes and pathways contribute to healthy functions of the posterior and anterior cingulate networks and disruptions to these functions may in turn contribute to the pathological and clinical events observed in Parkinson’s disease.