17 research outputs found
PSYCHIATRIC COMORBIDITIES IN PARKINSON\u27S DISEASE SEEN THROUGH THE PRISM OF GENOMICS AND EPIGENETICS
Parkinson\u27s disease (PD) is a neurodegenerative disorder clinically characterized by motor dysfunctions due to progressive loss
of dopaminergic neurons and a broad spectrum of non-motor symptoms. Interestingly, non-motor symptoms like depression, anxiety
and psychosis are often present several years before the occurrence of classic motor features seriously affecting patient quality of
life. Their presence is often misleading, delaying the correct diagnosis of PD. Despite its high incidence, the pathophysiology and
aetiology of neuropsychiatric symptoms associated with PD remains unclear. Currently, a lot of interest lays in research looking for
genetic predictors of motor and non-motor symptoms in PD. The availability of next-generation sequencing technology for genome,
epigenetic and transcriptional analysis opens the door to a new way of studying multifactorial diseases like PD and their
comorbidities. In this review we will present new insights in the genomic and epigenetic background of psychiatric comorbidity in
Parkinson\u27s disease
Genetski mehanizmi lizosomske disfunkcije u Parkinsonovoj bolesti [Genetic mechanisms of lysosomal dysfunction in Parkinson's disease]
Accumulation of misfolded proteins in the brain is the main pathological hallmark of neurodegenerative diseases, including Parkinsonās disease (PD), suggesting that inadequate clearance of aggregation-prone proteins plays an important role in the disease pathogenesis. Studies on the rare inherited forms of PD have highlighted disturbed alpha-synuclein clearance through the autophagy-lysosomal pathway (ALP) as a key mechanism leading to PD. In order to characterize the putative underlying genetic mechanisms leading to ALP dysfunction in PD, we performed comprehensive analysis of genetic variants in ALP genes in PD patients using the custom LYSOGENE targeted next-generation sequencing panel, containing a set of 440 ALP related genes, as well as genes previously implicated in familial forms of PD. We identified a significant number of ALP gene variants among PD patients when compared to control subjects. These variants were involved in over 50 biological processes, with the greatest enrichment observed in categories of lysosome organization, organic substance transport, abnormal myelination and sphingolipid metabolism. In contrast, variants found exclusively in healthy subjects were not related to specific biological pathways.
Based on the NGS data, we selected genes ARSD, GALC and LRBA with the most over-represented genetic variants in PD patients and investigated their effects on lysosomal impairment, alpha-synuclein accumulation and neurotoxicity using SH-SY5Y cell lines stably expressing human alpha-synuclein. The results were compared to the effects of the knock-down of a known lysosome-related gene, ATP13A2, which causes a rare autosomal recessive form of juvenile-onset atypical PD (PARK9). Our knock-down experiments described for the first time the association between ARSD and LRBA genes with the accumulation of aSyn and confirmed the association between GALC gene and PD. This study confirmed a link between lysosomal dysfunction and alpha-synuclein accumulation
DijagnostiÄke i terapijske nedoumice u lijeÄenju intrakranijskih aneurizma
Intracranial aneurysms have a prevalence of about 2% of the population. They are
a common incidental finding of noninvasive neuroimaging methods, raising the question of the necessity
of treatment of patients with an asymptomatic intracranial aneurysm. For long, the only treatment
option was surgical clipping of aneurysm neck. In the last 25 years, endovascular techniques have been
developed as an alternative solution for patients who are not eligible for neurosurgical procedures.
Research has shown better results of embolization procedures with lower rates of complications, but a
higher rate of recanalization is still a major drawback of endovascular coiling. There are no strict protocols
and the treatment of choice for intracranial aneurysms should be agreed upon by both the
physician and the patient. This review aims to provide an insight into the management of intracerebral
aneurysms with emphasis on the decision making problems faced by clinicians.Intrakranijske aneurizme prisutne su u oko 2% populacije. UobiÄajen su sluÄajni nalaz neinvazivnih neuroslikovnih metoda
otvarajuÄi pitanje nužnosti lijeÄenja bolesnika s asimptomatskom intrakranijskom aneurizmom. Dugo je jedina moguÄnost
lijeÄenja bila kirurÅ”ko podvezivanje vrata aneurizme, no u posljednjih 25 godina usavrÅ”en je endovaskularni pristup
pružajuÄi alternativu bolesnicima koji ne ispunjavaju uvjete za neurokirurÅ”ke zahvate. Istraživanja su pokazala bolje rezultate
embolizacijskih postupaka s nižim stopama komplikacija, ipak, veÄa stopa rekanalizacija i dalje je glavni nedostatak endovaskularnog
pristupa. Ne postoje strogi protokoli tretiranja intrakranijskih aneurizma te konaÄna odluka leži u dijalogu izmeÄu
lijeÄnika i bolesnika. Cilj ovoga preglednog rada jest pružiti uvid u pristup intracerebralnim aneurizmama s naglaskom na
probleme donoÅ”enja odluka s kojima se suoÄavaju kliniÄari
Evaluation of cerebrospinal fluid phosphorylated tau231 as a biomarker in the differential diagnosis of Alzheimer's disease and vascular dementia
BACKGROUND:
The diagnosis of either Alzheimer's disease (AD) or vascular dementia (VaD) is still largely based on clinical guidelines and exclusion of other diseases that may lead to dementia. ----- AIMS:
In this study, we assessed whether the use of sensitive and specific biomarkers such as phosphorylated tau proteins could contribute to an earlier and more accurate diagnosis of AD and VaD, as well as to their differentiation. ----- MATERIAL AND METHODS:
A total of 198 patients, of which 152 had AD, 28 VaD, and 18 were healthy controls (HC), were included in the analyses. We analyzed cerebrospinal fluid (CSF) levels of total tau protein (t-tau), tau protein phosphorylated at threonine 231 (p-tau231), and factor score (FS) determined by combination of p-tau231 and Mini-Mental State Examination (MMSE) in patients with AD and VaD, as well as in HC. We tested the diagnostic accuracy of these biomarkers in the CSF and FS (p-tau231, MMSE) in differentiating AD from VaD and HC. ----- RESULTS:
Total tau levels were significantly elevated in subjects with AD compared to HC, as well as in VaD subjects compared to HC. ----- DISCUSSION:
p-tau231 levels were significantly higher in patients with ADvsHC as well in patients with VaD vsHC. p-tau231 levels did not distinguish AD from VaD patients. Importantly, FS(p-tau231 and MMSE) showed statistically significant differences in the distribution of subjects with AD and VaD. ----- CONCLUSION:
These results indicate that FS (p-tau231 and MMSE) has a strong potential to provide an early distinction between AD and VaD
Genetic mechanisms of lysosomal dysfunction in Parkinson's disease
Glavni patoloÅ”ki znak Parkinsonove bolesti (PB) jest nakupljanje proteina alfa sinukleina (aSyn) Å”to sugerira da neuÄinkovita razgradnja proteina podložnih agregaciji igra važnu ulogu u patogenezi bolesti. Studije o rijetkim naslijeÄenim oblicima PB ukazale su na smanjenu razgradnju aSyn putem autofagno-lizosomalnog puta (ALP) kao jednog od kljuÄnih mehanizama u podlozi PB. Kako bismo karakterizirali pretpostavljene genetske mehanizme koji dovode do disfunkcije ALP-a u PB, proveli smo opsežnu analizu genetskih varijanti koriÅ”tenjem ciljanog panela za sekvenciranje pod nazivom LYSOGENE. LYSOGENE panel sadrţži sveobuhvatni skup od 440 ALP srodnih gena, kao i gene prethodno opisane u familijarnim oblicima PB, sinukleinopatijama i drugim neurodegenerativnim bolestima. Identificirali smo znaÄajan broj varijanti ALP gena meÄu PB pacijentima u usporedbi s kontrolnim ispitanicima, s 396 varijanti prisutnih iskljuÄivo u PB bolesnika. Ove varijante ukljuÄene su u viÅ”e od 50 bioloÅ”kih procesa, ponajprije u putovima organizacije lizosoma, transporta organskih tvari, abnormalne mijelinizacije i metabolizma sfingolipida. Suprotno tome, varijante koje su pronaÄene iskljuÄivo u zdravih ispitanika nisu bile povezane sa specifiÄnim bioloÅ”kim putovima. Na temelju podataka sekvenciranja, odabrali smo ARSD, GALC i LRBA gene s najviÅ”e zastupljenim genetskim varijantama kod pacijenata s PB i istražili njihove uÄinke na lizosomalno oÅ”teÄenje, akumulaciju aSyn i neurotoksiÄnost primjenom SH-SY5Y staniÄnih linija koje stabilno eksprimiraju ljudski aSyn. Rezultati su usporeÄeni s uÄincima utiÅ”avanja ATP13A2 gena za kojeg je opisano da dovodi do nakupljanja aSyn. NaÅ”i rezultati snažno upuÄuju na to da specifiÄne varijante ALP gena mogu doprinijeti lizosomalnoj disfunkciji u PB. Ovim istraživanjem je po prvi puta opisana povezanost utiÅ”avanja ARSD i LRBA gena s nakupljanjem aSyn proteina te potvrÄena povezanost utiÅ”avanja GALC gena s PB. Ovo istraživanje je potvrdilo vezu izmeÄu lizosomalnog oÅ”teÄenja i akumulacije aSyn.Accumulation of misfolded proteins in the brain is the main pathological hallmark of neurodegenerative diseases, including Parkinsonās disease (PD), suggesting that inadequate clearance of aggregation-prone proteins plays an important role in the disease pathogenesis. Studies on the rare inherited forms of PD have highlighted disturbed alpha-synuclein clearance through the autophagy-lysosomal pathway (ALP) as a key mechanism leading to PD. In order to characterize the putative underlying genetic mechanisms leading to ALP dysfunction in PD, we performed comprehensive analysis of genetic variants in ALP genes in PD patients using the custom LYSOGENE targeted next-generation sequencing panel, containing a set of 440 ALP related genes, as well as genes previously implicated in familial forms of PD. We identified a significant number of ALP gene variants among PD patients when compared to control subjects. These variants were involved in over 50 biological processes, with the greatest enrichment observed in categories of lysosome organization, organic substance transport, abnormal myelination and sphingolipid metabolism. In contrast, variants found exclusively in healthy subjects were not related to specific biological pathways.
Based on the NGS data, we selected genes ARSD, GALC and LRBA with the most over-represented genetic variants in PD patients and investigated their effects on lysosomal impairment, alpha-synuclein accumulation and neurotoxicity using SH-SY5Y cell lines stably expressing human alpha-synuclein. The results were compared to the effects of the knock-down of a known lysosome-related gene, ATP13A2, which causes a rare autosomal recessive form of juvenile-onset atypical PD (PARK9). Our knock-down experiments described for the first time the association between ARSD and LRBA genes with the accumulation of aSyn and confirmed the association between GALC gene and PD. This study confirmed a link between lysosomal dysfunction and alpha-synuclein accumulation
Genetic mechanisms of lysosomal dysfunction in Parkinson's disease
Glavni patoloÅ”ki znak Parkinsonove bolesti (PB) jest nakupljanje proteina alfa sinukleina (aSyn) Å”to sugerira da neuÄinkovita razgradnja proteina podložnih agregaciji igra važnu ulogu u patogenezi bolesti. Studije o rijetkim naslijeÄenim oblicima PB ukazale su na smanjenu razgradnju aSyn putem autofagno-lizosomalnog puta (ALP) kao jednog od kljuÄnih mehanizama u podlozi PB. Kako bismo karakterizirali pretpostavljene genetske mehanizme koji dovode do disfunkcije ALP-a u PB, proveli smo opsežnu analizu genetskih varijanti koriÅ”tenjem ciljanog panela za sekvenciranje pod nazivom LYSOGENE. LYSOGENE panel sadrţži sveobuhvatni skup od 440 ALP srodnih gena, kao i gene prethodno opisane u familijarnim oblicima PB, sinukleinopatijama i drugim neurodegenerativnim bolestima. Identificirali smo znaÄajan broj varijanti ALP gena meÄu PB pacijentima u usporedbi s kontrolnim ispitanicima, s 396 varijanti prisutnih iskljuÄivo u PB bolesnika. Ove varijante ukljuÄene su u viÅ”e od 50 bioloÅ”kih procesa, ponajprije u putovima organizacije lizosoma, transporta organskih tvari, abnormalne mijelinizacije i metabolizma sfingolipida. Suprotno tome, varijante koje su pronaÄene iskljuÄivo u zdravih ispitanika nisu bile povezane sa specifiÄnim bioloÅ”kim putovima. Na temelju podataka sekvenciranja, odabrali smo ARSD, GALC i LRBA gene s najviÅ”e zastupljenim genetskim varijantama kod pacijenata s PB i istražili njihove uÄinke na lizosomalno oÅ”teÄenje, akumulaciju aSyn i neurotoksiÄnost primjenom SH-SY5Y staniÄnih linija koje stabilno eksprimiraju ljudski aSyn. Rezultati su usporeÄeni s uÄincima utiÅ”avanja ATP13A2 gena za kojeg je opisano da dovodi do nakupljanja aSyn. NaÅ”i rezultati snažno upuÄuju na to da specifiÄne varijante ALP gena mogu doprinijeti lizosomalnoj disfunkciji u PB. Ovim istraživanjem je po prvi puta opisana povezanost utiÅ”avanja ARSD i LRBA gena s nakupljanjem aSyn proteina te potvrÄena povezanost utiÅ”avanja GALC gena s PB. Ovo istraživanje je potvrdilo vezu izmeÄu lizosomalnog oÅ”teÄenja i akumulacije aSyn.Accumulation of misfolded proteins in the brain is the main pathological hallmark of neurodegenerative diseases, including Parkinsonās disease (PD), suggesting that inadequate clearance of aggregation-prone proteins plays an important role in the disease pathogenesis. Studies on the rare inherited forms of PD have highlighted disturbed alpha-synuclein clearance through the autophagy-lysosomal pathway (ALP) as a key mechanism leading to PD. In order to characterize the putative underlying genetic mechanisms leading to ALP dysfunction in PD, we performed comprehensive analysis of genetic variants in ALP genes in PD patients using the custom LYSOGENE targeted next-generation sequencing panel, containing a set of 440 ALP related genes, as well as genes previously implicated in familial forms of PD. We identified a significant number of ALP gene variants among PD patients when compared to control subjects. These variants were involved in over 50 biological processes, with the greatest enrichment observed in categories of lysosome organization, organic substance transport, abnormal myelination and sphingolipid metabolism. In contrast, variants found exclusively in healthy subjects were not related to specific biological pathways.
Based on the NGS data, we selected genes ARSD, GALC and LRBA with the most over-represented genetic variants in PD patients and investigated their effects on lysosomal impairment, alpha-synuclein accumulation and neurotoxicity using SH-SY5Y cell lines stably expressing human alpha-synuclein. The results were compared to the effects of the knock-down of a known lysosome-related gene, ATP13A2, which causes a rare autosomal recessive form of juvenile-onset atypical PD (PARK9). Our knock-down experiments described for the first time the association between ARSD and LRBA genes with the accumulation of aSyn and confirmed the association between GALC gene and PD. This study confirmed a link between lysosomal dysfunction and alpha-synuclein accumulation
Genetic mechanisms of lysosomal dysfunction in Parkinson's disease
Glavni patoloÅ”ki znak Parkinsonove bolesti (PB) jest nakupljanje proteina alfa sinukleina (aSyn) Å”to sugerira da neuÄinkovita razgradnja proteina podložnih agregaciji igra važnu ulogu u patogenezi bolesti. Studije o rijetkim naslijeÄenim oblicima PB ukazale su na smanjenu razgradnju aSyn putem autofagno-lizosomalnog puta (ALP) kao jednog od kljuÄnih mehanizama u podlozi PB. Kako bismo karakterizirali pretpostavljene genetske mehanizme koji dovode do disfunkcije ALP-a u PB, proveli smo opsežnu analizu genetskih varijanti koriÅ”tenjem ciljanog panela za sekvenciranje pod nazivom LYSOGENE. LYSOGENE panel sadrţži sveobuhvatni skup od 440 ALP srodnih gena, kao i gene prethodno opisane u familijarnim oblicima PB, sinukleinopatijama i drugim neurodegenerativnim bolestima. Identificirali smo znaÄajan broj varijanti ALP gena meÄu PB pacijentima u usporedbi s kontrolnim ispitanicima, s 396 varijanti prisutnih iskljuÄivo u PB bolesnika. Ove varijante ukljuÄene su u viÅ”e od 50 bioloÅ”kih procesa, ponajprije u putovima organizacije lizosoma, transporta organskih tvari, abnormalne mijelinizacije i metabolizma sfingolipida. Suprotno tome, varijante koje su pronaÄene iskljuÄivo u zdravih ispitanika nisu bile povezane sa specifiÄnim bioloÅ”kim putovima. Na temelju podataka sekvenciranja, odabrali smo ARSD, GALC i LRBA gene s najviÅ”e zastupljenim genetskim varijantama kod pacijenata s PB i istražili njihove uÄinke na lizosomalno oÅ”teÄenje, akumulaciju aSyn i neurotoksiÄnost primjenom SH-SY5Y staniÄnih linija koje stabilno eksprimiraju ljudski aSyn. Rezultati su usporeÄeni s uÄincima utiÅ”avanja ATP13A2 gena za kojeg je opisano da dovodi do nakupljanja aSyn. NaÅ”i rezultati snažno upuÄuju na to da specifiÄne varijante ALP gena mogu doprinijeti lizosomalnoj disfunkciji u PB. Ovim istraživanjem je po prvi puta opisana povezanost utiÅ”avanja ARSD i LRBA gena s nakupljanjem aSyn proteina te potvrÄena povezanost utiÅ”avanja GALC gena s PB. Ovo istraživanje je potvrdilo vezu izmeÄu lizosomalnog oÅ”teÄenja i akumulacije aSyn.Accumulation of misfolded proteins in the brain is the main pathological hallmark of neurodegenerative diseases, including Parkinsonās disease (PD), suggesting that inadequate clearance of aggregation-prone proteins plays an important role in the disease pathogenesis. Studies on the rare inherited forms of PD have highlighted disturbed alpha-synuclein clearance through the autophagy-lysosomal pathway (ALP) as a key mechanism leading to PD. In order to characterize the putative underlying genetic mechanisms leading to ALP dysfunction in PD, we performed comprehensive analysis of genetic variants in ALP genes in PD patients using the custom LYSOGENE targeted next-generation sequencing panel, containing a set of 440 ALP related genes, as well as genes previously implicated in familial forms of PD. We identified a significant number of ALP gene variants among PD patients when compared to control subjects. These variants were involved in over 50 biological processes, with the greatest enrichment observed in categories of lysosome organization, organic substance transport, abnormal myelination and sphingolipid metabolism. In contrast, variants found exclusively in healthy subjects were not related to specific biological pathways.
Based on the NGS data, we selected genes ARSD, GALC and LRBA with the most over-represented genetic variants in PD patients and investigated their effects on lysosomal impairment, alpha-synuclein accumulation and neurotoxicity using SH-SY5Y cell lines stably expressing human alpha-synuclein. The results were compared to the effects of the knock-down of a known lysosome-related gene, ATP13A2, which causes a rare autosomal recessive form of juvenile-onset atypical PD (PARK9). Our knock-down experiments described for the first time the association between ARSD and LRBA genes with the accumulation of aSyn and confirmed the association between GALC gene and PD. This study confirmed a link between lysosomal dysfunction and alpha-synuclein accumulation
PSYCHIATRIC COMORBIDITIES IN PARKINSON\u27S DISEASE SEEN THROUGH THE PRISM OF GENOMICS AND EPIGENETICS
Parkinson\u27s disease (PD) is a neurodegenerative disorder clinically characterized by motor dysfunctions due to progressive loss
of dopaminergic neurons and a broad spectrum of non-motor symptoms. Interestingly, non-motor symptoms like depression, anxiety
and psychosis are often present several years before the occurrence of classic motor features seriously affecting patient quality of
life. Their presence is often misleading, delaying the correct diagnosis of PD. Despite its high incidence, the pathophysiology and
aetiology of neuropsychiatric symptoms associated with PD remains unclear. Currently, a lot of interest lays in research looking for
genetic predictors of motor and non-motor symptoms in PD. The availability of next-generation sequencing technology for genome,
epigenetic and transcriptional analysis opens the door to a new way of studying multifactorial diseases like PD and their
comorbidities. In this review we will present new insights in the genomic and epigenetic background of psychiatric comorbidity in
Parkinson\u27s disease