Development of an Alpha-synuclein Based Rat Model for Parkinson's Disease via Stereotactic Injection of a Recombinant Adeno-associated Viral Vector

Perren, Anke Van der; Casteels, Cindy; Laere, Koen Van; Gijsbers, Rik; Haute, Chris Van den; Baekelandt, Veerle

doi:10.3791/53670

Cited by 11 publications

(12 citation statements)

References 24 publications

(23 reference statements)

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“…One advantage of cellular models is that they offer unique opportunities to apply advanced imaging and omics approaches to elucidate in great detail the key events associated with α-syn aggregation and LB formation and maturation and to correlate these events with alteration in cellular pathways and functions/dysfunctions. Until recently, the great majority of cellular models of synucleinopathies were based on overexpression of WT or mutant α-syn alone, with other proteins, or coupled to treatment with other stress inducers (e.g., toxins, proteasome inhibitors) [9][10][11][12][13][14][15][16][17][18][19] . In many cases, these conditions were sufficient to induce α-syn accumulation and aggregation.…”

Section: Introductionmentioning

confidence: 99%

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Mahul‐Mellier

Burtscher

Maharjan

et al. 2019

Preprint

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Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LB). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD and synucleinopathies, the processes that govern α-syn fibrillization and LB formation in the brain remain poorly understood. In this work, we sought to reverse engineer LBs and dissect the spatiotemporal events involved in their biogenesis at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we took advantage of a seeding-based model of α-syn fibril formation in primary neurons and further developed this model to generate the first neuronal model that reproduces the key events leading to LB formation; including seeding, fibrillization, and the formation of LB-like inclusions that recapitulate many of the biochemical, structural, and organizational features of LBs found in post-mortem human PD brain tissues. Next, we applied an integrative approach combining confocal and correlative light-electron microscopy (CLEM) imaging methods with biochemical profiling of α-syn species and temporal proteomic and transcriptomic analyses to dissect the molecular events associated with LB formation and maturation and to elucidate their contributions to neuronal dysfunctions and neurodegeneration in PD and synucleinopathies. The results from these studies demonstrate that LB formation involves a complex interplay between α-syn fibrillization, post-translational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria and the autophagosome and endolysosome. Furthermore, we demonstrate that the process of LB formation and maturation, rather than simply fibril formation, is the major driver of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, as well as synaptic dysfunctions. Having a neuronal model that allows for unlinking of the key processes involved in LB formation is crucial for elucidating the molecular and cellular determinants of each process and their contributions to neuronal dysfunction and degeneration in PD and synucleinopathies. Such a model is essential to efforts to identify and investigate the mode of action and toxicity of drug candidates targeting α-syn aggregation and LB formation.

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Section: Introductionmentioning

confidence: 99%

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Mahul‐Mellier

Burtscher

Maharjan

et al. 2019

Preprint

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“…Overexpression of human WT α-synuclein or PD-associated mutants, such as A53T, A30P, S129A, and S129D α-synuclein, have triggered characteristics associated with PD, including dopamine neuron loss, reduced dopamine content, motor impairments, and neuroinflammation [ 179 ]. rAAV-α-synuclein can be injected into rat or mouse brains to induce the PD models, providing a choice to test whether certain genes affect neurodegeneration synergistically with α-synuclein [ 185 ]. The PFF model is established by injecting α-synuclein fibrils into the brain to act as a seed to recruit endogenous α-synuclein, leading to the formation of larger aggregates that exert toxic effects on the affected neurons [ 186 , 187 ].…”

Section: Snca (Park1/park4)mentioning

confidence: 99%

“…Overexpression of human WT α-synuclein or PDassociated mutants, such as A53T, A30P, S129A, and S129D α-synuclein, have triggered characteristics associated with PD, including dopamine neuron loss, reduced dopamine content, motor impairments, and neuroinflammation [179]. rAAV-α-synuclein can be injected into rat or mouse brains to induce the PD models, providing a choice to test whether certain genes affect neurodegeneration synergistically with α-synuclein [185].…”

Section: Snca (Park1/park4)mentioning

confidence: 99%

Comprehensive Perspectives on Experimental Models for Parkinson’s Disease

Chong

Zhu

et al. 2021

Aging and disease

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“…[143][144][145]171 Consistently, elevating a-synuclein levels in the SN in rodents through viral expression results in neurodegeneration and behavior deficits. [172][173][174][175] Dysfunction of a-synuclein is widely regarded as central to PD pathogenesis triggering abnormalities, including defective synaptic vesicle fusion and DA release, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, induction of the unfolded protein response, and autophagy-lysosomal pathway impairment. 176,177 It has recently been discovered that misfolded a-synuclein can be transferred from one cell to another spreading disease pathology in a prion-like manner.…”

Section: Age-associated Neurodegenerative Diseasesmentioning

confidence: 99%

Overdosing on iron: Elevated iron and degenerative brain disorders

D’Mello¹,

Kindy

2020

Exp Biol Med (Maywood)

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All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

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Development of an Alpha-synuclein Based Rat Model for Parkinson's Disease via Stereotactic Injection of a Recombinant Adeno-associated Viral Vector

Cited by 11 publications

References 24 publications

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Comprehensive Perspectives on Experimental Models for Parkinson’s Disease

Overdosing on iron: Elevated iron and degenerative brain disorders

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