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Aims: Parkinson's disease (PD) is frequently associated with a prodromal sensory neuropathy manifesting with sensory loss and chronic pain. We have recently shown that PD-associated sensory neuropathy in patients is associated with high levels of glucosylceramides. Here, we assessed the underlying pathology and mechanisms in Pink1−/−SNCAA53T double mutant mice. Methods: We studied nociceptive and olfactory behaviour and the neuropathology of dorsal root ganglia (DRGs), including ultrastructure, mitochondrial respiration, transcriptomes, outgrowth and calcium currents of primary neurons, and tissue ceramides and sphingolipids before the onset of a PD-like disease that spontaneously develops in Pink1−/−SNCAA53T double mutant mice beyond 15 months of age. Results: Similar to PD patients, Pink1−/−SNCAA53T mice developed a progressive prodromal sensory neuropathy with a loss of thermal sensitivity starting as early as 4 months of age. In analogy to human plasma, lipid analyses revealed an accumulation of glucosylceramides (GlcCer) in the DRGs and sciatic nerves, which was associated with pathological mitochondria, impairment of mitochondrial respiration, and deregulation of transient receptor potential channels (TRPV and TRPA) at mRNA, protein and functional levels in DRGs. Direct exposure of DRG neurons to GlcCer caused transient hyperexcitability, followed by a premature decline of the viability of sensory neurons cultures upon repeated GlcCer application. Conclusions: The results suggest that pathological GlcCer contribute to prodromal sensory disease in PD mice via mitochondrial damage and calcium channel hyperexcitability. GlcCer-associated sensory neuron pathology might be amenable to GlcCer lowering therapeutic strategies.
Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our “hub-spoke” model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.
Longitudinal changes of cortical microstructure in Parkinson's disease assessed with T1 relaxometry
(2016)
Background: Histological evidence suggests that pathology in Parkinson's disease (PD) goes beyond nigrostriatal degeneration and also affects the cerebral cortex. Quantitative MRI (qMRI) techniques allow the assessment of changes in brain tissue composition. However, the development and pattern of disease-related cortical changes have not yet been demonstrated in PD with qMRI methods. The aim of this study was to investigate longitudinal cortical microstructural changes in PD with quantitative T1 relaxometry.
Methods: 13 patients with mild to moderate PD and 20 matched healthy subjects underwent high resolution T1 mapping at two time points with an interval of 6.4 years (healthy subjects: 6.5 years). Data from two healthy subjects had to be excluded due to MRI artifacts. Surface-based analysis of cortical T1 values was performed with the FreeSurfer toolbox.
Results: In PD patients, a widespread decrease of cortical T1 was detected during follow-up which affected large parts of the temporo-parietal and occipital cortices and also frontal areas. In contrast, age-related T1 decrease in the healthy control group was much less pronounced and only found in lateral frontal, parietal and temporal areas. Average cortical T1 values did not differ between the groups at baseline (p = 0.17), but were reduced in patients at follow-up (p = 0.0004). Annualized relative changes of cortical T1 were higher in patients vs. healthy subjects (patients: − 0.72 ± 0.64%/year; healthy subjects: − 0.17 ± 0.41%/year, p = 0.007).
Conclusions: In patients with PD, the development of widespread changes in cortical microstructure was observed as reflected by a reduction of cortical T1. The pattern of T1 decrease in PD patients exceeded the normal T1 decrease as found in physiological aging and showed considerable overlap with the pattern of cortical thinning demonstrated in previous PD studies. Therefore, cortical T1 might be a promising additional imaging marker for future longitudinal PD studies. The biological mechanisms underlying cortical T1 reductions remain to be further elucidated.
Im Rahmen dieser Abschlussarbeit zur Erlangung des Magister Artium an der Johann Wolfgang Goethe-Universität Frankfurt am Main wurde ein apparativ gestützter Gangtest zur Analyse neurologischer Krankheitsbilder an einer Stichprobe Morbus Parkinson erkrankter Probanden (n = 28) und einer Kontrollgruppe (n = 9) erprobt. Bei diesem sogenannten Adaptationstest variiert die Laufbandgeschwindigkeit während der Testdauer von 5:28 min in definierten Zeitabständen um unterschiedlich große positive und negative Beträge in einem Bereich von 1,4 km/h bis 3,3 km/h, (SCHWED ET AL. 2005). Die Fähigkeit der Adaptation an äußere Einflüsse und wechselnde Umweltbedingungen ist bei Morbus Parkinson durch neuropathologische und pathophysiologische Veränderungen erheblich erschwert bzw. gestört (vgl. CONRAD 1998, MORRIS ET AL. 1999 & 2001, SCHARF & WEINECK 2004, SCHWED ET AL. 2005). Die Beurteilung dieser Adaptationsfähigkeit ist mittels bestehender Ganganalyseverfahren nicht möglich. Die Applikation eines extern auferlegten Rhythmuszwanges (Metronom, Laufbandgeschwindigkeit) ermöglicht nach EBERSBACH ET AL. (1999, 619ff) die Feststellung gangmotorischer Abnormitäten, die bei freier Gangmusterwahl nicht erkennbar sind. Dies äußert sich beispielsweise in einer gesteigerten Schritt-zu-Schritt Variabilität bei Parkinson-Patienten, die auf eine Störung der periodisch lokomotorischen Aktivitätserzeugung (engl.: periodic locomotor activity generation) hindeuten (EBERSBACH ET AL. 1999, 619ff). In der vorliegenden Untersuchung wurden mit einem apparativ gestützten biomechanischen Verfahren die Positionsveränderungen der Probanden auf den acht-sekündigen Geschwindigkeitsstufen in Folge der Geschwindigkeitswechsel mittels verschiedener Kennwerte untersucht. Ergänzend wurden klinische Daten erhoben. Über den Verlauf des gesamten Testes zeigten sich bei den berechneten Streuungsmaßen jeder Geschwindigkeitsstufe signifikant (p < .05) bis hoch signifikant (p < .01) höhere Kennwerte auf Seiten der Morbus Parkinson-Gruppe. Bei Betrachtung der einzelnen Stufen fanden sich signifikant bis hoch signifikant höhere Kennwerte für die Morbus Parkinson-Gruppe bei größeren Sprüngen (³ 0,4 km/h) auf höhere Geschwindigkeiten (³ 2,4 km/h). Die Signifikanzen traten nahezu ausschließlich in der zweiten Testhälfte in dem Geschwindigkeitsbereich mit der höchsten Durchschnittsgeschwindigkeit von 3,0 km/h auf. Die nicht antizipierbare positive oder negative Variation der Laufbandgeschwindigkeit stellt hohe Anforderungen an propriozeptive und sensomotorische Reflexsysteme (vgl. SCHWED ET AL. 2005). Die Störung dieser Systeme konnte in dieser Untersuchung durch den Nachweis vermehrter und größerer Positionsveränderungen der Parkinson-Patienten nach Wechseln der Laufbandgeschwindigkeit im Vergleich zur Kontrollgruppe belegt werden. Die vermehrten Unterschiede in der zweiten Testhälfte könnten auf parkinson-typische Konzentrationsschwächen oder vorzeitige Ermüdungserscheinungen hindeuten. Die Ausdifferenzierung des Testsettings und der Auswertungsstrategie bringt sicherlich weitere diagnostische Möglichkeiten und Erkenntnisse mit sich. Die Anwendung der grundlegenden Methode, in für den Probanden nicht antizipierbaren ständig wechselnden Laufbandgeschwindigkeiten, könnte zudem in der Gangtherapie von neurologischen Krankheitsbildern Einsatz finden. In der von SCHARF UND WEINECK (2004, 128) geforderten Schulung der Auswahl von Gangmustern unter möglichst vielen verschiedenen Bewegungssituationen bei Parkinson-Patienten, bietet der Adaptationstest eine nützliche und ökonomische Anwendungsmöglichkeit. Stürze sind bei Parkinson-Patienten auf Grund der Symptomkonstellationen (posturale Instabilität, Bradykinese, Festination, Freezing, usw.) häufig und ziehen mitunter schwere Verletzungen nach sich. Weitere Einschränkungen der Aktivitäten des täglichen Lebens (ADL) und Verschlechterungen der Lebensqualität sind die Folge. In sogenannten „Jahrmarktsituationen“ (häufiges Abstoppen, Losgehen, Bremsen, Beschleunigen) geben Parkinson-Patienten verstärkt Unsicherheiten an. Es ist daher wichtig den Patienten ein breites Übungsrepertoire anzubieten, auf das sie im Notfall zurück greifen können (SCHARF & WEINECK 2004, 128). Die Aktivierung des, bei Morbus Parkinson geschädigten, dopaminergen Systems wird nach SCHULTZ (1998) durch neuartige Stimuli und nicht antizipierbare Reize erreicht. Anwendungsfelder des Adaptationstestes bieten sich in diagnostischen und therapeutischen Bereichen. Die Ausdifferenzierung der Methoden sollte weiter verfolgt werden.
The family of lysosome-associated membrane proteins (LAMP) includes the ubiquitously expressed LAMP1 and LAMP2, which account for half of the proteins in the lysosomal membrane. Another member of the LAMP family is LAMP3, which is expressed only in certain cell types and differentiation stages. LAMP3 expression is linked with poor prognosis of certain cancers, and the locus where it is encoded was identified as a risk factor for Parkinson's disease (PD). Here, we investigated the role of LAMP3 in the two main cellular degradation pathways, the proteasome and autophagy. LAMP3 mRNA was not detected in mouse models of PD or in the brain of human patients. However, it was strongly induced upon proteasomal inhibition in the neuroblastoma cell line SH-SY5Y. Induction of LAMP3 mRNA following proteasomal inhibition was dependent on UPR transcription factor ATF4 signaling and induced autophagic flux. Prevention of LAMP3 induction enhanced apoptotic cell death. In summary, these data demonstrate that LAMP3 regulation as part of the UPR contributes to protein degradation and cell survival during proteasomal dysfunction. This link between autophagy and the proteasome may be of special importance for the treatment of tumor cells with proteasomal inhibitors.
Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues.