Viral Vector Mediated Overexpression of Human <i>α</i>-Synuclein in the Nigrostriatal Dopaminergic Neurons: A New Model for Parkinson's Disease

Maingay, Matthew; Romero‐Ramos, Marina; Kirik, Deniz

doi:10.1017/s1092852900010075

Cited by 31 publications

(18 citation statements)

References 97 publications

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“…4L). Consistent with observations in postmortem PD brain tissue (49,50), it has been shown that the A10 neurons of the VTA are less affected by AAV-mediated α-syn overexpression than the A9 nigral neurons (51). We hypothesized that more efficient protein clearance by the ALP may confer a unique resistance to this subpopulation of DA midbrain neurons against α-syn-induced toxicity.…”

Section: -H)supporting

confidence: 74%

TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity

Decressac

Mattsson

Weikop

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

648

615

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The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of α-synuclein oligomers, and were aggravated by microRNA-128-mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synucleininduced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.adeno-associated virus | Beclin | aggregates | synucleinopathy A major hallmark of Parkinson disease (PD) that contributes to the progressive loss of nigral dopamine (DA) neurons is α-synucleinopathy. Defects in clearance of oligomeric or misfolded proteins have been associated with aging and several neurodegenerative disorders (1-4). In human PD and related Lewy Body diseases, the presence of α-synuclein-positive (α-syn + ) aggregates is associated with accumulation of autophagosomes and reduction of lysosomal markers in affected nigral DA neurons, suggesting a defect in lysosome-mediated clearance of α-syn aggregates (5-7).How dysfunction of the autophagy-lysosome pathway (ALP) contributes to the pathogenesis of PD remains unclear. Under physiological conditions, α-syn is degraded by the ubiquitinproteasome system and the ALP, including macroautophagy and chaperone-mediated autophagy (6,(8)(9)(10)(11)(12). In cases of α-syn overload, however, misfolded or mutated α-syn fails to be processed and α-syn clearance by chaperone-mediated autophagy is blocked (12)(13)(14)(15). In this situation, processing of excess α-syn, or toxic α-syn species, will depend on the functional integrity of the macroautophagy pathway (14). In support, it has been shown that mice deficient in one of the autophagy-related (atg) proteins develop neurodegeneration, and that deficiency in atg7 or the PD-associated protein PARK9 (ATP13A2, a lysosomal ATPase) causes PD-like neurodegeneration, both in vitro and in vivo (7,(16)(17)(18)(19). In humans, PD has been genetically linked to the rare lysosomal storage diseases, Gaucher disease a...

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Section: -H)supporting

confidence: 74%

TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity

Decressac

Mattsson

Weikop

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

648

615

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“…A53T mutant ␣-syn is reported to accelerate fibril formation compared with wild-type ␣-syn in vitro (Conway et al, 1998). In the transgenic mice, A53T mutant ␣-syn is also revealed to cause greater neurotoxicity than wild-type ␣-syn Maingay et al, 2005;Dawson et al, 2010). In our model, coexpression of A53T mutant ␣-syn and GFP developed overt degeneration of dopaminergic neurons.…”

Section: Discussionmentioning

confidence: 99%

Authentically Phosphorylated α-Synuclein at Ser129 Accelerates Neurodegeneration in a Rat Model of Familial Parkinson's Disease

Sato¹,

Arawaka²,

Hara³

et al. 2011

J. Neurosci.

118

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Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the appearance of fibrillar aggregates of insoluble ␣-synuclein (␣-syn) called Lewy bodies (LBs). Approximately 90% of ␣-syn deposited in LBs is phosphorylated at serine 129 (Ser129). In contrast, only 4% of total ␣-syn is phosphorylated in normal brain, suggesting that accumulation of Ser129-phosphorylated ␣-syn is involved in the pathogenesis of PD. However, the role of Ser129 phosphorylation in ␣-syn neurotoxicity remains unclear. In this study, we coexpressed familial PD-linked A53T ␣-syn and G-protein-coupled receptor kinase 6 (GRK6) in the rat SN pars compacta using recombinant adeno-associated virus 2. Coexpression of these proteins yielded abundant Ser129-phosphorylated ␣-syn and significantly exacerbated degeneration of dopaminergic neurons when compared with coexpression of A53T ␣-syn and GFP. Immunohistochemical analysis revealed that Ser129-phosphorylated ␣-syn was preferentially distributed to swollen neurites. However, biochemical analysis showed that the increased expression of Ser129-phosphorylated ␣-syn did not promote accumulation of detergentinsoluble ␣-syn. Coexpression of catalytically inactive K215R mutant GRK6 failed to accelerate A53T ␣-syn-induced degeneration. Furthermore, introducing a phosphorylation-incompetent mutation, S129A, into A53T ␣-syn did not alter the pace of degeneration, even when GRK6 was coexpressed. Our study demonstrates that authentically Ser129-phosphorylated ␣-syn accelerates A53T ␣-syn neurotoxicity without the formation of detergent-insoluble ␣-syn, and suggests that the degenerative process could be constrained by inhibiting the kinase that phosphorylates ␣-syn at Ser129.

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“…Furthermore, the ability to efficiently target the photoreceptor and RPE cells of the retina bilaterally suggests this technology can be used to generate primate animal models of retinal degeneration. 23 For example, a novel transgenesis approach based not on germ line transgenesis, but instead harnessing AAV vectors to overexpress causative, mutant RP genes in the photoreceptors of models such as the macaque, could offer an attractive strategy to generate primate models of retinal degeneration. 24 …”

Section: Introductionmentioning

confidence: 99%

Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9

et al. 2011

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Delivery of therapeutic genes to a large region of the retina with minimal damage from intraocular surgery is a central goal of treatment for retinal degenerations. Recent studies have shown that AAV9 can reach the central nervous system (CNS) and retina when administered systemically to neonates, which is a promising strategy for some retinal diseases. We investigated whether the retinal transduction efficiency of systemically delivered AAV9 could be improved by mutating capsid surface tyrosines, previously shown to increase the infectivity of several AAV vectors. Specifically, we evaluated retinal transduction following neonatal intravascular administration of AAV9 vectors containing tyrosine to phenylalanine mutations at two highly conserved sites. Our results show that a novel, double tyrosine mutant of AAV9 significantly enhanced gene delivery to the CNS and retina, and that gene expression can be restricted to rod photoreceptor cells by incorporating a rhodopsin promoter. This approach provides a new methodology for the development of retinal gene therapies or creation of animal models of neurodegenerative disease.

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Viral Vector Mediated Overexpression of Human α-Synuclein in the Nigrostriatal Dopaminergic Neurons: A New Model for Parkinson's Disease

Cited by 31 publications

References 97 publications

TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity

TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity

Authentically Phosphorylated α-Synuclein at Ser129 Accelerates Neurodegeneration in a Rat Model of Familial Parkinson's Disease

Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9

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