# Spatial transcriptomics reveals the molecular signatures of prodromal and advanced α-synucleinopathy **Authors:** Lin Lin, Nanna M. Jensen, Alberto Delaidelli, Sara A. Ferreira, Fatemeh Yarmahmoudi, Poul H. Sorensen, Marina Romero-Ramos, Poul H. Jensen, Ian R. Mackenzie, Jens R. Nyengaard, Asad Jan PMC · DOI: 10.1016/j.isci.2026.114845 · iScience · 2026-01-29 ## TL;DR The study uses spatial transcriptomics to uncover molecular changes in a mouse model of Parkinson's disease, revealing potential biomarkers and therapeutic targets. ## Contribution The study identifies novel molecular signatures associated with early and advanced stages of α-synuclein pathology in Parkinson's disease. ## Key findings - Induction of α-synuclein pathology in rodent brain stimulates mitochondrial metabolism. - Declining energy metabolism and mRNA translation herald the onset of motor defects. - Aberrant ROCK2 and SPP1 signaling reflect progressive tissue damage. ## Abstract A pathological role of α-synuclein (aSyn) aggregation in the etiology of Parkinson disease (PD) is well established. Here, we applied spatial transcriptomics (ST) on brain sections derived from a rodent mouse model of α-synucleinopathy (transgenic M83+/+ line). Our ST data revealed that induction of aSyn pathology in the brainstem of rodents triggered upregulation of pathways controlling energy metabolism. At a later stage, characterized by movement disability, the ST data indicated a drastic downregulation of mitochondrial metabolic pathways along with perturbed expression of mRNA translation machinery. Furthermore, analyses of microarrays datasets derived from 4 independent cohorts of PD patients led to the identification of aberrant osteopontin (SPP1) signaling and increased expression of CREB-binding protein as consistent markers associated with the progression of aSyn pathology in the rodent model and in PD brains. We anticipate that our findings hold promise for biomarker discovery and/or mechanism-based therapies in PD and related neurodegenerative disorders. •Induction of α-Synuclein pathology in rodent brain stimulates mitochondrial metabolism•Declining energy metabolism and mRNA translation herald the onset of motor defects•Aberrant ROCK2 and SPP1 signaling reflect progressive tissue damage•Increased CREBBP expression is a unique marker of advanced α-synuclein pathology Induction of α-Synuclein pathology in rodent brain stimulates mitochondrial metabolism Declining energy metabolism and mRNA translation herald the onset of motor defects Aberrant ROCK2 and SPP1 signaling reflect progressive tissue damage Increased CREBBP expression is a unique marker of advanced α-synuclein pathology Model organism; Molecular neuroscience; Protein structure aspects; Transcriptomics ## Linked entities - **Genes:** SPP1 (secreted phosphoprotein 1) [NCBI Gene 6696], CREBBP (CREB binding lysine acetyltransferase) [NCBI Gene 1387], ROCK2 (Rho associated coiled-coil containing protein kinase 2) [NCBI Gene 9475] - **Diseases:** Parkinson disease (MONDO:0005180) - **Species:** Mus musculus (taxon 10090) ## Full-text entities - **Genes:** Slc18a2 (solute carrier family 18 (vesicular monoamine), member 2) [NCBI Gene 214084] {aka 1110037L13Rik, 9330105E13, Vmat2}, Grn (granulin) [NCBI Gene 14824] {aka GP88, PCDGF, PEPI, Pgrn, epithelin}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, Ep300 (E1A binding protein p300) [NCBI Gene 328572] {aka A430090G16, A730011L11, KAT3B, p300, p300 HAT}, Ache (acetylcholinesterase) [NCBI Gene 11423], Prnp (prion protein) [NCBI Gene 19122] {aka CD230, PrP, PrP, PrPC, PrPSc, Prn-i}, Mobp (myelin-associated oligodendrocytic basic protein) [NCBI Gene 17433] {aka MOBP155, MOBP170, MOBP69, MOBP73, MOBP81}, Tph2 (tryptophan hydroxylase 2) [NCBI Gene 216343] {aka Ntph}, Kcnj10 (potassium inwardly-rectifying channel, subfamily J, member 10) [NCBI Gene 16513] {aka BIR10, BIRK-1, Kir1.2, Kir4.1}, Rpl34 (ribosomal protein L34) [NCBI Gene 68436] {aka 1100001I22Rik}, SPP1 (secreted phosphoprotein 1) [NCBI Gene 6696] {aka BNSP, BSPI, ETA-1, OPN}, Elavl4 (ELAV like RNA binding protein 4) [NCBI Gene 15572] {aka Elav, Hud, PNEM}, ND4L (NADH dehydrogenase subunit 4L) [NCBI Gene 17720], Cartpt (CART prepropeptide) [NCBI Gene 27220] {aka Cart}, Gpr37 (G protein-coupled receptor 37) [NCBI Gene 14763] {aka Pael-R}, Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56717] {aka 2610315D21Rik, FRAP, FRAP2, Frap1, RAFT1, RAPT1}, Rock1 (Rho-associated coiled-coil containing protein kinase 1) [NCBI Gene 19877] {aka 1110055K06Rik, Rock-I}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 22339] {aka L-VEGF, Vegf, Vpf}, Rock2 (Rho-associated coiled-coil containing protein kinase 2) [NCBI Gene 19878] {aka B230113H15Rik, ROKalpha, Rho-kinase, Rock-II, Rock2m, mKIAA0619}, App (amyloid beta precursor protein) [NCBI Gene 11820] {aka Abeta, Abpp, Adap, Ag, Cvap, E030013M08Rik}, Pag1 (phosphoprotein associated with glycosphingolipid microdomains 1) [NCBI Gene 94212] {aka Cbp, F730007C19Rik, Pag}, Nufip2 (nuclear FMR1 interacting protein 2) [NCBI Gene 68564] {aka 1110001M19Rik, 9530056D24Rik, PIG1, mKIAA1321}, Nts (neurotensin) [NCBI Gene 67405] {aka 5033428E16Rik, NMN-125, NN, NT, NT/N, NTS1}, Nrxn3 (neurexin III) [NCBI Gene 18191], Eef2 (eukaryotic translation elongation factor 2) [NCBI Gene 13629] {aka Ef-2}, Pkm (pyruvate kinase, muscle) [NCBI Gene 18746] {aka Pk-2, Pk-3, Pk3, Pkm2}, SNCA (synuclein alpha) [NCBI Gene 6622] {aka NACP, PARK1, PARK4, PD1}, Ncam1 (neural cell adhesion molecule 1) [NCBI Gene 17967] {aka CD56, E-NCAM, NCAM-1, Ncam}, Cdk4 (cyclin dependent kinase 4) [NCBI Gene 12567] {aka Crk3}, Adcyap1 (adenylate cyclase activating polypeptide 1) [NCBI Gene 11516] {aka PACAP}, Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, Lrrc17 (leucine rich repeat containing 17) [NCBI Gene 74511] {aka 37kDa, 4833425M04Rik, 6130400C22Rik, P37nb}, Snca (synuclein, alpha) [NCBI Gene 20617] {aka NACP, alpha-Syn, alphaSYN}, Scg2 (secretogranin II) [NCBI Gene 20254] {aka Chgc, SgII}, Adcy1 (adenylate cyclase 1) [NCBI Gene 432530] {aka AC1, D11Bwg1392e, I-AC, brl}, Rpl9 (ribosomal protein L9) [NCBI Gene 20005], Slc2a4 (solute carrier family 2 (facilitated glucose transporter), member 4) [NCBI Gene 20528] {aka GT2, Glut-4, Glut4, twgy}, Matk (megakaryocyte-associated tyrosine kinase) [NCBI Gene 17179] {aka CHK, HYL, Ntk, p56ntk}, Rps2 (ribosomal protein S2) [NCBI Gene 16898] {aka Llrep3, S4}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, ATP8 (ATP synthase F0 subunit 8) [NCBI Gene 17706], Per1 (period circadian clock 1) [NCBI Gene 18626] {aka Hftm, Per, m-rigui, mPer1}, CREBBP (CREB binding lysine acetyltransferase) [NCBI Gene 1387] {aka CBP, KAT3A, MKHK1, RSTS, RSTS1}, Pgap6 (post-glycosylphosphatidylinositol attachment to proteins 6) [NCBI Gene 60455] {aka GPI-PLA2, M83, Rxylt1, Tmem8, Tmem8a}, Clock (clock circadian regulator) [NCBI Gene 12753] {aka 5330400M04Rik, KAT13D}, Dcn (decorin) [NCBI Gene 13179] {aka DC, DSPG2, PG40, PGII, PGS2, SLRR1B}, Igf1 (insulin-like growth factor 1) [NCBI Gene 16000] {aka C730016P09Rik, Igf-1, Igf-I}, Kras (Kras proto-oncogene, GTPase) [NCBI Gene 16653] {aka K-Ras, K-Ras 2, K-ras, Ki-ras, Kras-2, Kras2}, Kit (Kit proto-oncogene receptor tyrosine kinase) [NCBI Gene 16590] {aka Bs, CD117, Fdc, Gsfsco1, Gsfsco5, Gsfsow3}, Hsp90b1 (heat shock protein 90, beta (Grp94), member 1) [NCBI Gene 22027] {aka ERp99, GRP94, TA-3, Targ2, Tra-1, Tra1}, Gabarapl1 (GABA type A receptor associated protein like 1) [NCBI Gene 57436] {aka 3110025G09Rik, 9130422N19Rik, Apg8l, Atg8l, GECI, MNCb-0091}, Crebbp (CREB binding protein) [NCBI Gene 12914] {aka CBP, CBP/p300, KAT3A, p300/CBP}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Creb1 (cAMP responsive element binding protein 1) [NCBI Gene 12912] {aka 2310001E10Rik, 3526402H21Rik, Creb, Creb-1}, Psap (prosaposin) [NCBI Gene 19156] {aka SGP-1}, Scd2 (stearoyl-Coenzyme A desaturase 2) [NCBI Gene 20250] {aka Mir5114, Scd-2, mir-5114, swty}, Ndn (necdin, MAGE family member) [NCBI Gene 17984] {aka Peg6}, Cox5b (cytochrome c oxidase subunit 5B) [NCBI Gene 12859], Col1a1 (collagen, type I, alpha 1) [NCBI Gene 12842] {aka Col1a-1, Cola-1, Cola1, Mov-13, Mov13}, Apod (apolipoprotein D) [NCBI Gene 11815] - **Diseases:** metabolic syndrome (MESH:D024821), inflammatory (MESH:D007249), neurodegeneration (MESH:D019636), mitochondrial deficiency (MESH:D028361), PD (MESH:D010300), pain (MESH:D010146), sleep disorder (MESH:D012893), weakness (MESH:D018908), CAPITAL (MESH:D060048), neurotoxic (MESH:D020258), AD (MESH:D000544), neuroinflammation (MESH:D000090862), DM (MESH:D009223), alpha-synucleinopathy (MESH:D000080874), Multiple system atrophy (MESH:D019578), neurological deficit (MESH:D009461), autonomic (MESH:D001342), insulin resistance (MESH:D007333), ES (MESH:D012512), hindlimb paresis (MESH:D010291), T2DM (MESH:D003924), axonal degeneration (MESH:D009410), parkinsonism (MESH:D010302), dementia (MESH:D003704), Lewy (MESH:D018827), LS (MESH:D007888), CNS injury (MESH:D002494), ST (MESH:D008569), motor defects (MESH:D000068079), motor disability (MESH:D009069), tissue damage (MESH:D017695), neuronal apoptosis (MESH:D065703) - **Chemicals:** methanol (MESH:D000432), paraffin (MESH:D010232), OCT (MESH:C051883), nitrogen (MESH:D009584), FITC (MESH:D016650), Triton-X (MESH:D017830), 6-hydroxydopamine (MESH:D016627), water (MESH:D014867), biotin (MESH:D001710), blood glucose (MESH:D001786), cholesterol (MESH:D002784), oxalic acid (MESH:D019815), DPI-75 (-), hematoxylin (MESH:D006416), fatty acid (MESH:D005227), potassium permanganate (MESH:D011196), rotenone (MESH:D012402), neuromelanin (MESH:C014121), ATP (MESH:D000255), melanin (MESH:D008543), lipid (MESH:D008055), Paraformaldehyde (MESH:C003043), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MESH:D015632), DAB (MESH:C000469), Heparin (MESH:D006493), dopamine (MESH:D004298), PBS (MESH:D007854), reactive oxygen species (MESH:D017382), Cy5 (MESH:C085321), DAPI (MESH:C007293), formalin (MESH:D005557), glucose (MESH:D005947) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Drosophila melanogaster (fruit fly, species) [taxon 7227] - **Mutations:** serine/threonine, A53T - **Cell lines:** BL21(DE3) — Mus musculus (Mouse), Hybridoma (CVCL_B7HM) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12927100/full.md ## Figures 7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12927100/full.md ## References 77 references — full list in the complete paper: https://tomesphere.com/paper/PMC12927100/full.md --- Source: https://tomesphere.com/paper/PMC12927100