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Boosting chaperone-...
Boosting chaperone-mediated autophagy in vivo mitigates alpha-synuclein-induced neurodegeneration
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Xilouri, Maria (författare)
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Brekk, Oeystein Roed (författare)
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- Landeck, Natalie (författare)
- Lund University,Lunds universitet,Brain Repair and Imaging in Neural Systems (BRAINS),Forskargrupper vid Lunds universitet,Lund University Research Groups
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Pitychoutis, Pothitos M. (författare)
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Papasilekas, Themistoklis (författare)
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Papadopoulou-Daifoti, Zoi (författare)
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- Kirik, Deniz (författare)
- Lund University,Lunds universitet,Brain Repair and Imaging in Neural Systems (BRAINS),Forskargrupper vid Lunds universitet,Lund University Research Groups
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Stefanis, Leonidas (författare)
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(creator_code:org_t)
- 2013-06-11
- 2013
- Engelska.
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 136, s. 2130-2146
- Relaterad länk:
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http://dx.doi.org/10...
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https://academic.oup...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- alpha-Synuclein levels are critical to Parkinson's disease pathogenesis. Wild-type alpha-synuclein is degraded partly by chaperone-mediated autophagy, and aberrant alpha-synuclein may act as an inhibitor of the pathway. To address whether the induction of chaperone-mediated autophagy may represent a potential therapy against alpha-synuclein-induced neurotoxicity, we overexpressed lysosomal-associated membrane protein 2a, the rate-limiting step of chaperone-mediated autophagy, in human neuroblastoma SH-SY5Y cells, rat primary cortical neurons in vitro, and nigral dopaminergic neurons in vivo. Overexpression of the lysosomal-associated membrane protein 2a in cellular systems led to upregulation of chaperone-mediated autophagy, decreased alpha-synuclein turnover, and selective protection against adenoviral-mediated wild-type alpha-synuclein neurotoxicity. Protection was observed even when the steady-state levels of alpha-synuclein were unchanged, suggesting that it occurred through the attenuation of alpha-synuclein-mediated dysfunction of chaperone-mediated autophagy. Overexpression of the lysosomal receptor through the nigral injection of recombinant adeno-associated virus vectors effectively ameliorated alpha-synuclein-induced dopaminergic neurodegeneration by increasing the survival of neurons located in the substantia nigra as well as the axon terminals located in the striatum, which was associated with a reduction in total alpha-synuclein levels and related aberrant species. We conclude that induction of chaperone-mediated autophagy may provide a novel therapeutic strategy in Parkinson's disease and related synucleinopathies through two different mechanisms: amelioration of dysfunction of chaperone-mediated autophagy and lowering of alpha-synuclein levels.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Nyckelord
- alpha-synuclein
- chaperone-mediated autophagy
- Lamp2a
- neurotoxicity
- Parkinson's disease
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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