Adeno-Associated Viral Vectors as Versatile Tools for Parkinson’s Research, Both for Disease Modeling Purposes and for Therapeutic Uses

Fajardo-Serrano, Ana; Rico, Alberto J.; Roda, Elvira; Honrubia, Adriana; Arrieta, Sandra; Ariznabarreta, Goiaz; Chocarro, Julia; Lorenzo-Ramos, Elena; Pejenaute, Álvaro; Vázquez, Armando González; Lanciego, José L.

doi:10.3390/ijms22126389

Cited by 16 publications

(10 citation statements)

References 175 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, there are some limitations despite the obvious utility of the AAV10 model reported herein. The AAV vectors represent versatile tools, both for disease modeling purposes and therapeutic uses [38,39]. When designing any given AAV-based experiment in the brain field, a number of important items regarding the AAV structure itself need to be taken into consideration, namely the selection of the best suited AAV serotype together with the choice of the most convenient promoter (e.g., the sequence driving transgene expression).…”

Section: Discussionmentioning

confidence: 99%

Up and Down γ-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice

Pavia-Collado

Rodríguez-Aller

Alarcón-Arís

et al. 2022

IJMS

View full text Add to dashboard Cite

The synuclein family consists of α-, β-, and γ-Synuclein (α-Syn, β-Syn, and γ-Syn) expressed in the neurons and concentrated in synaptic terminals. While α-Syn is at the center of interest due to its implication in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, limited information exists on the other members. The current study aimed at investigating the biological role of γ-Syn controlling the midbrain dopamine (DA) function. We generated two different mouse models with: (i) γ-Syn overexpression induced by an adeno-associated viral vector and (ii) γ-Syn knockdown induced by a ligand-conjugated antisense oligonucleotide, in order to modify the endogenous γ-Syn transcription levels in midbrain DA neurons. The progressive overexpression of γ-Syn decreased DA neurotransmission in the nigrostriatal and mesocortical pathways. In parallel, mice evoked motor deficits in the rotarod and impaired cognitive performance as assessed by novel object recognition, passive avoidance, and Morris water maze tests. Conversely, acute γ-Syn knockdown selectively in DA neurons facilitated forebrain DA neurotransmission. Importantly, modifications in γ-Syn expression did not induce the loss of DA neurons or changes in α-Syn expression. Collectively, our data strongly suggest that DA release/re-uptake processes in the nigrostriatal and mesocortical pathways are partially dependent on substantia nigra pars compacta /ventral tegmental area (SNc/VTA) γ-Syn transcription levels, and are linked to modulation of DA transporter function, similar to α-Syn.

show abstract

Section: Discussionmentioning

confidence: 99%

Up and Down γ-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice

Pavia-Collado

Rodríguez-Aller

Alarcón-Arís

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…The use of non-pathogenic adeno-associated virus (AAV) vectors has emerged as an effective and safe approach for both preclinical modeling and therapeutic methods for neurological disorders ( Bourdenx et al, 2014 ; Deverman et al, 2018 ; Hudry and Vandenberghe, 2019 ; Nectow and Nestler, 2020 ; Fajardo-Serrano et al, 2021 ). In particular, specific serotypes of AAV, such as recombinant adeno-associated virus serotype 9 (AAV9) and pseudotype rhesus-10 (AAVrh.10), have shown unique properties to target the central nervous system (CNS) in comparison to most AAV serotypes ( Foust et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Pilot Study Assessing the Impact of Intrathecal Administration of Variants AAV-PHP.B and AAV-PHP.eB on Brain Transduction in Adult Rhesus Macaques

Arotcarena

Doveró

Biendon

et al. 2021

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

Adeno-associated virus (AAV) vectors are increasingly used as an effective and safe approach to deliver genetic material to the central nervous system (CNS). The AAV9-derived variants, AAV-PHP. B and AAV-PHP.eB, reportedly broadly transduce cells throughout the CNS compared to the original serotype 9, AAV9. As non-human primate data are scarce, we here evaluated the CNS transduction efficiencies after lumbar intrathecal bolus delivery of identical doses of either AAV-PHP. B:CAG-EGFP or AAV-PHP. eB:CAG-EGFP in rhesus macaque monkeys. AAV-PHP.eB achieved a more efficient and widespread CNS transduction compared to AAV-PHP.B. We report a strong neuronal and oligodendroglial tropism for both variants in the putamen and in the hippocampus. This proof-of-concept experiment highlights the potential value of intrathecal infusions of AAV-PHP.eB to distribute genetic material in the CNS with cell-type specificity and introduces a new opportunity to model brain diseases in rhesus macaque monkeys and further develop gene therapies targeting the CNS in humans.

show abstract

“…Among the strategies used to modify gene expression in the CNS, the use of viral vectors has been explored [ 195 ], in particular adeno-associated virus (AAV) [ 196 , 197 ]. in In addition to LRRK2 knock-out mice, recombinant AAVs (rAVVs) were employed to overexpress α-syn in LRRK2 wild-type and G2019S mutated animal models of PD.…”

Section: Lrrk2 As a Therapeutic Target For Pdmentioning

confidence: 99%

LRRK2 and Proteostasis in Parkinson’s Disease

Pérez-Carrión

Posadas

Solera

et al. 2022

IJMS

View full text Add to dashboard Cite

Parkinson’s disease is a neurodegenerative condition initially characterized by the presence of tremor, muscle stiffness and impaired balance, with the deposition of insoluble protein aggregates in Lewy’s Bodies the histopathological hallmark of the disease. Although different gene variants are linked to Parkinson disease, mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are one of the most frequent causes of Parkinson’s disease related to genetic mutations. LRRK2 toxicity has been mainly explained by an increase in kinase activity, but alternative mechanisms have emerged as underlying causes for Parkinson’s disease, such as the imbalance in LRRK2 homeostasis and the involvement of LRRK2 in aggregation and spreading of α-synuclein toxicity. In this review, we recapitulate the main LRRK2 pathological mutations that contribute to Parkinson’s disease and the different cellular and therapeutic strategies devised to correct LRRK2 homeostasis. In this review, we describe the main cellular control mechanisms that regulate LRRK2 folding and aggregation, such as the chaperone network and the protein-clearing pathways such as the ubiquitin–proteasome system and the autophagic-lysosomal pathway. We will also address the more relevant strategies to modulate neurodegeneration in Parkinson’s disease through the regulation of LRRK2, using small molecules or LRRK2 silencing.

show abstract

Adeno-Associated Viral Vectors as Versatile Tools for Parkinson’s Research, Both for Disease Modeling Purposes and for Therapeutic Uses

Cited by 16 publications

References 175 publications

Up and Down γ-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice

Up and Down γ-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice

Pilot Study Assessing the Impact of Intrathecal Administration of Variants AAV-PHP.B and AAV-PHP.eB on Brain Transduction in Adult Rhesus Macaques

LRRK2 and Proteostasis in Parkinson’s Disease

Contact Info

Product

Resources

About