Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Abstract

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 ...

Interferon-γ signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem cells

“…With regard to PD, there is evidence for a link between expression network signatures of disease loci and IFN type II—also known as IFN-γ— signaling 4 . Recently, IFN-γ signaling has also been linked to the selective vulnerability of dopaminergic (DA) neurons 5 .…”

Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia

“…However, increasing evidence indicate that dysregulation of IFN signaling plays a role in ageing and neurodegenerative disease processes 2,3,4 . With respect to PD, genetic and functional studies have identified a link between IFN-γ and disease 5,6,11,13,14,15 . There is also considerable evidence that PD genes can synergize with inflammatory triggers in determining disease risk 16,49,50 .…”

“…With regard to PD, there is evidence for a link between expression network signatures of disease loci and IFN-γ signaling 5 . Recently, IFN-γ response has also been linked to the selective vulnerability of dopaminergic (DA) neurons 6 . IFN-γ is a cytokine primarily produced by T-lymphocytes and natural killer cells as part of the immune response against pathogens 7 .…”

Genetic Risk Profiling in Parkinson’s Disease and Utilizing Genetics to Gain Insight into Disease-Related Biological Pathways

“…This approach also revealed that these genes underwent developmental stage-specific and cell type-specific interactions in several neurobiological disorders, demonstrating how greater functional understanding of GWAS signals can be achieved when they are considered in their cellular context. Another recent study identified PD-relevant pathways via analysis of co-expressed modules of genes, the expression of which was perturbed in brain regions susceptible to PD [ 44 ].…”