Parkinson’s disease as a multisystem disorder: whole transcriptome study in Parkinson’s disease patients’ skin and blood
Date
2021-05-07
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Abstract
Alzheimeri tõve järel on Parkinsoni tõbi (PT) teine kõige levinum neurodegeneratiivne haigus, mille puhul esineb arvestatavalt palju kliinilist valediagnoosi. PT on liigutushäire, millele on iseloomulik tahtlike liigutuste aeglus (mida tuntakse bradükineesiana), rigiidsus ja rahutreemor, mida kokku nimetatakse parkinsoni triaadiks. PT patofüsioloogiale on iseloomulik dopaminergiliste närvirakkude hävimine kesknärvisüsteemi mustaines ja närvirakkudes patoloogilise valgu α-sünukleiini kuhjumine Lewy kehakesteks. Kindla diagnoosi saab anda alles peale surma, sest hetkel pole PT jaoks olemas usaldusväärseid biomarkereid. Enamik PT juhtumitest on sporaadilised ja suured genoomiülesed uuringud näitavad, et ainuüksi geenide varieeruvus ei ole PT peamine esinemise põhjus. Seetõttu uurib käesolev teadustöö PT geeniekspressiooni (transkriptoomikat), et leida kasutavaid diagnostilisi ja prognostilisi biomarkerid. Geeniekspressiooni koespetsiifilisuse tõttu on transkriptoomika puhul oluline, millisest koest proov võtta. PT on kanooniliselt keskaju dopaminergiliste närvirakkude haigus, kuid sellest koest ei saa eluspuhuselt proovi võtta. Arvestades, et transkriptoomikat saab keskajust teha ainult peale surma, on teiste ligipääsetavate kudede leidmine eluspuhuseks diagnostikaks oluline. Potentsiaalsete huvipakkuvate kudede alla võib lugeda naha, sest PT patsientidel esineb üldpopulatsioonist rohkem melanoomi ning teisi spetsiifilisi nahaprobleeme. Naha kõrval on teine huvipakkuv kude veri, sest see on kõige lihtsamini kogutav kude ja ringeldes kogu organismis, sisaldab ta endas palju süsteemset informatsiooni. Selgitamaks, kas PT on multisüsteemne haigus, kus on haigusspetsiifiliselt muutunud ka mitteneuronaalsed perifeersed koed, on käesoleva töö eesmärgiks kaardistada PT geeniekspressiooni RNA sekveneerimise abil nahas ja veres. PT naha tulemused näitavad, et valdava osa geenide ekspressioon on alla reguleeritud ja leitud muutused peegeldavad PT ajukoes leitud mustrit. Samuti selgitavad need muutused naha kõrgemat haavatavust mutageensete ohtude suhtes, mis võib põhjendada kõrgenenud melanoomi esinemist PT põdevate inimeste nahas. Teadustöö viitab sellele, et PT võib muuta naha kui perifeerse koe geeniekspressiooni haigusspetsiifiliselt. Tulemused PT põdevate inimeste vereproovidest näitavad oluliselt vähem muutusi, mida samas on varasemate PT uuringutes juba kirjeldatud. Muutuste vähesuse tõttu on verd raske kasutada biomarkerite avastamiseks, sest tegemist on heterogeense koega ja tulemused ei pruugi seega olla reprodutseeritavad. Kahe koe võrdluses ei leitud kattuvaid oluliselt muutunud geeniekspressioone. See asjaolu rõhutab koespetsiifiliste erinevuste tähtsust geeniekspressiooni uuringutes. Käesolev uuring toob välja geeniekspressioonid, mis näitasid kõige reprodutseeritavamaid muutusi ja vajavad täiendavaid funktsionaalseid uuringuid nende biomarkeripotentsiaali hindamiseks.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease with a considerable rate of clinical misdiagnosis. PD is a movement disorder characterized by slowness of voluntary movement (known as bradykinesia), rigidity and resting tremor, together known as the parkinsonian triad. The pathophysiology of PD converges into pathognomonic loss of dopaminergic neurons in substantia nigra of the central nervous system and the accumulation of pathologic protein α-synuclein into Lewy bodies in neurons. The definite diagnosis can only be established post mortem, as there are currently no reliable biomarkers for PD. Most PD cases are sporadic and large genome wide association studies show that gene variance alone is not the main cause of PD occurrence. This work, therefore, investigates gene expression (transcriptomics) of PD in search of feasible diagnostic and prognostic biomarkers. The tissue which the sample is taken from is relevant in transcriptomics, because gene expression is tissue specific. PD has canonically seen as a disease of the dopaminergic neurons in the central nervous tissue, but this tissue cannot be sampled from living patients. It is, therefore, necessary to find other tissues that allow sampling in vivo for biomarker research. A potential tissue of interest is the skin because PD patients have more melanoma and other specific skin conditions compared to the general population. Another promising tissue next to skin is the blood, because it is the easiest to sample and circulating the whole organism carries a lot of systemic information. The current work profiles gene expression from skin and blood using RNA sequencing in order to explore the disease specific involvement of nonneuronal peripheral tissues in PD. The results from PD skin show a pattern of global downregulation of differentially expressed genes that mirrors the pathophysiology of PD in the brain. Changes that lead to vulnerability in PD skin to mutagenic hazards are also mapped that might explain the epidemiologically observed elevated prevalence of melanoma in PD patients. This suggests that gene expression in the skin, a peripheral nonneuronal tissue, is PD-specifically changed. The results from PD blood show notably fewer changes, however, most are previously described in PD. This highlights the difficulty in using blood for biomarker discovery as the tissue is heterogeneous and the results are not easily reproducible. No overlapping differentially changed gene expressions are found in comparison of the two tissues in PD, which underlines the importance of tissue specific differences in gene expression. The study highlights notable differential gene expressions that show most robust changes and warrant further functional studies to evaluate their biomarker potential.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease with a considerable rate of clinical misdiagnosis. PD is a movement disorder characterized by slowness of voluntary movement (known as bradykinesia), rigidity and resting tremor, together known as the parkinsonian triad. The pathophysiology of PD converges into pathognomonic loss of dopaminergic neurons in substantia nigra of the central nervous system and the accumulation of pathologic protein α-synuclein into Lewy bodies in neurons. The definite diagnosis can only be established post mortem, as there are currently no reliable biomarkers for PD. Most PD cases are sporadic and large genome wide association studies show that gene variance alone is not the main cause of PD occurrence. This work, therefore, investigates gene expression (transcriptomics) of PD in search of feasible diagnostic and prognostic biomarkers. The tissue which the sample is taken from is relevant in transcriptomics, because gene expression is tissue specific. PD has canonically seen as a disease of the dopaminergic neurons in the central nervous tissue, but this tissue cannot be sampled from living patients. It is, therefore, necessary to find other tissues that allow sampling in vivo for biomarker research. A potential tissue of interest is the skin because PD patients have more melanoma and other specific skin conditions compared to the general population. Another promising tissue next to skin is the blood, because it is the easiest to sample and circulating the whole organism carries a lot of systemic information. The current work profiles gene expression from skin and blood using RNA sequencing in order to explore the disease specific involvement of nonneuronal peripheral tissues in PD. The results from PD skin show a pattern of global downregulation of differentially expressed genes that mirrors the pathophysiology of PD in the brain. Changes that lead to vulnerability in PD skin to mutagenic hazards are also mapped that might explain the epidemiologically observed elevated prevalence of melanoma in PD patients. This suggests that gene expression in the skin, a peripheral nonneuronal tissue, is PD-specifically changed. The results from PD blood show notably fewer changes, however, most are previously described in PD. This highlights the difficulty in using blood for biomarker discovery as the tissue is heterogeneous and the results are not easily reproducible. No overlapping differentially changed gene expressions are found in comparison of the two tissues in PD, which underlines the importance of tissue specific differences in gene expression. The study highlights notable differential gene expressions that show most robust changes and warrant further functional studies to evaluate their biomarker potential.
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Keywords
neurodegenerative diseases, Parkinson disease, gene expression, skin, blood, ribonucleic acid, nucleotide sequence, biomarkers