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Endogenous and treatment-induced neuroplasticity in mouse models of Parkinson's disease

Bez, Francesco LU (2016)
Abstract
Parkinson´s disease (PD) is an age-related neurodegenerative disorder characterized by a loss of nigral dopamine (DA) neurons that project their axons to the striatum. Striatal DA depletion causes the typical motor symptoms of PD. Another key feature of PD are intracellular protein inclusions containing alpha-synuclein within affected brain regions. L-DOPA is the most effective treatment for the symptoms of PD, although it causes debilitating long-term complications (L-DOPA-induced dyskinesia). There is a pressing need to identify therapeutic approaches that can stop or slow down the progression of PD.
The first part of this thesis aims at evaluating potential disease-modifying treatments based on stimulating the Sigma-1 receptor, an... (More)
Parkinson´s disease (PD) is an age-related neurodegenerative disorder characterized by a loss of nigral dopamine (DA) neurons that project their axons to the striatum. Striatal DA depletion causes the typical motor symptoms of PD. Another key feature of PD are intracellular protein inclusions containing alpha-synuclein within affected brain regions. L-DOPA is the most effective treatment for the symptoms of PD, although it causes debilitating long-term complications (L-DOPA-induced dyskinesia). There is a pressing need to identify therapeutic approaches that can stop or slow down the progression of PD.
The first part of this thesis aims at evaluating potential disease-modifying treatments based on stimulating the Sigma-1 receptor, an intracellular protein involved in cell repair and neuroplasticity. In the first and second study, mice sustained a lesion of nigrostriatal DA neurons using the toxin 6-OHDA, and were then treated daily with the sigma-1 receptor agonists PRE-084 (first study) or ANAVEX 2-73 (second study). Both compounds induced a gradual and substantial motor recovery over 5 weeks of treatment. This was associated with an induction of neuroplasticity markers, increased density of DA fibers, and reduced inflammation in the nigrostriatal DA pathway.
Another major aim of this thesis was to assess endogenous plasticity mechanisms in mouse models of PD during ageing. In the third study, mice sustained a 6-OHDA-lesion in young adulthood and were aged to 12 or 24 months. Other mice sustained the lesion at the advanced age of 23 months (comparable in age to a 70 year-old human being). Mice in the 12- and 24-months groups showed a spontaneous recovery of motor functions, associated with pronounced sprouting of dopaminergic and serotonergic axons into the striatum. These results reveal that ageing does not interfere with the plasticity of a damaged nigrostriatal DA pathway. However, ageing increased the susceptibility to L-DOPA-induced dyskinesia acutely after the nigrostriatal lesion.
Ageing conditions were also taken into account when studying transgenic mice overexpressing human alpha-synuclein. In these mice, ageing was associated with a progressive accumulation of alpha-synuclein in several brain regions. Despite this accumulation, the nigrostriatal DA pathway appeared structurally intact. Treatment of 18 months-old transgenic mice with the DA receptor agonist, apomorphine, induced a peculiar pattern of involuntary movements associated with abnormal regulation of ERK1/2 signaling in the striatum. We conclude that an overexpression of human alpha-synuclein can cause changes in striatal signaling even at an early symptomatic stage of PD-like pathology.
In summary, this thesis reveals that pharmacological stimulation of Sigma-1 receptors can boost neuroplasticity and promote recovery after nigrostriatal DA lesions. The second part of the thesis contributes novel findings about the relationship between behavioral impairments, PD-like pathology, and nigrostriatal plasticity in different mouse models of PD. (Less)
Abstract (Swedish)
Parkinsons sjukdom (PD) är den näst vanligast förekommande åldersrelaterade neurodegenerativa sjukdomen efter Alzheimers. De främsta symptomen på PD är typiska rörelsesvårigheter, vilka beror på förlust av dopamin i hjärnregionen striatum. Ett annat viktigt särdrag är ansamlingar av proteinet alpha-synuclein i många nervceller inom flera hjärnområden. Den effektivaste behandlingen mot Parkinson-symptom är L-DOPA. Den är tyvärr bara effektiv under några år och ger sedan upphov till komplikationer, så som onormala ofrivilliga rörelser (L-DOPA-inducerad dyskinesi). Det finns ett stort behov av att utveckla terapier som kan skydda känsliga nervceller och bromsa Parkinsons sjukdomsförlopp.
Avhandlingens första del avser att utvärdera en ny... (More)
Parkinsons sjukdom (PD) är den näst vanligast förekommande åldersrelaterade neurodegenerativa sjukdomen efter Alzheimers. De främsta symptomen på PD är typiska rörelsesvårigheter, vilka beror på förlust av dopamin i hjärnregionen striatum. Ett annat viktigt särdrag är ansamlingar av proteinet alpha-synuclein i många nervceller inom flera hjärnområden. Den effektivaste behandlingen mot Parkinson-symptom är L-DOPA. Den är tyvärr bara effektiv under några år och ger sedan upphov till komplikationer, så som onormala ofrivilliga rörelser (L-DOPA-inducerad dyskinesi). Det finns ett stort behov av att utveckla terapier som kan skydda känsliga nervceller och bromsa Parkinsons sjukdomsförlopp.
Avhandlingens första del avser att utvärdera en ny behandlingsprincip för att främja hjärnans förmåga till återhämtning och självläkning (‘neuroplasticitet’) efter en Parkinson-liknande skada. I den första och andra delstudien utvärderade vi substanser som ökar aktiviteten av Sigma-1 receptor, ett protein beläget inuti cellerna som främjar flera reparationsprocesser. Möss utsattes för en skada av dopamin-nervceller och behandlades med antingen PRE-084 (studie 1) eller ANAVEX 2-73 (studie 2) under 5 veckors tid. I både studierna resulterade behandlingen i en gradvis och markant förbättring av motoriska svårigheter. Symptomförbättringen hängde ihop med en ökning av dopamin-producerande nervtrådar i striatum, samt en minskning av inflammatoriska markörer.
Avhandlingens andra del avser att studera den inneboende förmågan till neuroplasticitet i parkinsonistiska möss med frågeställningen, hur denna förmåga påverkas av åldrandet. I den tredje delstudien utsattes unga möss för en toxisk skada av dopamin-producerande nervceller och testades vid olika åldrar. Ytterligare en grupp möss utsattes för samma skada vid 23 månaders ålder (motsvarande 70 år för människor). Ett av huvudfynden i denna studie var att åldrandet inte påverkar kapaciteten för strukturell och funktionell återhämtning i dopamin-producerande nervbanor. Utöver detta uppfann vi att en Parkinson-liknande dopaminskada i avancerad ålder hänger ihop med en ökad benägenhet till att utveckla onormala ofrivilliga rörelser vid behandling med L-DOPA.
Andra åldrandeförhållanden togs med i beräkningarna för att studera transgena möss som överuttrycker alpha-synuclein. Här hängde åldrandet ihop med ett ökat uttryck av alpha-synuclein, och med en försämrad motorisk funktion, trots intakta dopamin-producerande banor. När mössen hade uppnått 18 månader (och uppvisade enbart milda motoriska svårigheter) behandlades de med en dopamin-härmande substans (apomorfin). Behandlingen framkallade ofrivilliga röreselse som hängde ihop med ett förändrat mönster av cellsignalering i striatum. Dessa resultat visar att överuttryck av alpha-synuclein leder till ett förändrat svar på dopamin-härmande behandlingar. Den transgena alpha-synuclein musmodellen kan därför användas för att undersöka plastiska förändringar i ett tidigt stadium av Parkinson.
Sammanfattningsvis bidrar denna avhandling med nya fynd avseende den terapeutiska potentialen av att stimulera hjärnans plasticitet via sigma-1 receptorn. Vi visar nämligen att denna sorts behandling har både nervcellskyddande och symptom-förbättrande effekter en musmodell av Parkinson. Utöver dessa resultat bidrar avhandlingen till en ökad förståelse av åldrandets effekter på både patologin och neuroplasticitet i olika djurmodeller för Parkinsons sjukdom. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Steece-Collier, Kethy, Michigan State University
organization
publishing date
type
Thesis
publication status
published
subject
pages
98 pages
publisher
Lund University: Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17, Lund.
defense date
2016-10-14 13:15:00
ISBN
978-91-7619-341-9
language
English
LU publication?
yes
additional info
ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2016:115
id
d1c9b3a8-77d7-49b9-9b43-0c65323fa668
date added to LUP
2016-09-19 18:07:30
date last changed
2019-11-19 13:49:13
@phdthesis{d1c9b3a8-77d7-49b9-9b43-0c65323fa668,
  abstract     = {Parkinson´s disease (PD) is an age-related neurodegenerative disorder characterized by a loss of nigral dopamine (DA) neurons that project their axons to the striatum. Striatal DA depletion causes the typical motor symptoms of PD. Another key feature of PD are intracellular protein inclusions containing alpha-synuclein within affected brain regions. L-DOPA is the most effective treatment for the symptoms of PD, although it causes debilitating long-term complications (L-DOPA-induced dyskinesia). There is a pressing need to identify therapeutic approaches that can stop or slow down the progression of PD. <br/>The first part of this thesis aims at evaluating potential disease-modifying treatments based on stimulating the Sigma-1 receptor, an intracellular protein involved in cell repair and neuroplasticity. In the first and second study, mice sustained a lesion of nigrostriatal DA neurons using the toxin 6-OHDA, and were then treated daily with the sigma-1 receptor agonists PRE-084 (first study) or ANAVEX 2-73 (second study). Both compounds induced a gradual and substantial motor recovery over 5 weeks of treatment. This was associated with an induction of neuroplasticity markers, increased density of DA fibers, and reduced inflammation in the nigrostriatal DA pathway. <br/>Another major aim of this thesis was to assess endogenous plasticity mechanisms in mouse models of PD during ageing. In the third study, mice sustained a 6-OHDA-lesion in young adulthood and were aged to 12 or 24 months. Other mice sustained the lesion at the advanced age of 23 months (comparable in age to a 70 year-old human being). Mice in the 12- and 24-months groups showed a spontaneous recovery of motor functions, associated with pronounced sprouting of dopaminergic and serotonergic axons into the striatum. These results reveal that ageing does not interfere with the plasticity of a damaged nigrostriatal DA pathway. However, ageing increased the susceptibility to L-DOPA-induced dyskinesia acutely after the nigrostriatal lesion.<br/>Ageing conditions were also taken into account when studying transgenic mice overexpressing human alpha-synuclein. In these mice, ageing was associated with a progressive accumulation of alpha-synuclein in several brain regions. Despite this accumulation, the nigrostriatal DA pathway appeared structurally intact. Treatment of 18 months-old transgenic mice with the DA receptor agonist, apomorphine, induced a peculiar pattern of involuntary movements associated with abnormal regulation of ERK1/2 signaling in the striatum. We conclude that an overexpression of human alpha-synuclein can cause changes in striatal signaling even at an early symptomatic stage of PD-like pathology.<br/>In summary, this thesis reveals that pharmacological stimulation of Sigma-1 receptors can boost neuroplasticity and promote recovery after nigrostriatal DA lesions. The second part of the thesis contributes novel findings about the relationship between behavioral impairments, PD-like pathology, and nigrostriatal plasticity in different mouse models of PD.},
  author       = {Bez, Francesco},
  isbn         = {978-91-7619-341-9},
  language     = {eng},
  publisher    = {Lund University: Faculty of Medicine},
  school       = {Lund University},
  title        = {Endogenous and treatment-induced neuroplasticity in mouse models of Parkinson's disease},
  year         = {2016},
}