Boosting chaperone-mediated autophagy in vivo mitigates -synuclein-induced neurodegeneration

Article (PDF Available)inBrain 136(7) · June 2013with41 Reads
DOI: 10.1093/brain/awt131 · Source: PubMed
Abstract
α-Synuclein levels are critical to Parkinson's disease pathogenesis. Wild-type α-synuclein is degraded partly by chaperone-mediated autophagy, and aberrant α-synuclein may act as an inhibitor of the pathway. To address whether the induction of chaperone-mediated autophagy may represent a potential therapy against α-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 α-synuclein turnover, and selective protection against adenoviral-mediated wild-type α-synuclein neurotoxicity. Protection was observed even when the steady-state levels of α-synuclein were unchanged, suggesting that it occurred through the attenuation of α-synuclein-mediated dysfunction of chaperone-mediated autophagy. Overexpression of the lysosomal receptor through the nigral injection of recombinant adeno-associated virus vectors effectively ameliorated α-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 α-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 α-synuclein levels.

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Available from: Maria Xilouri, Dec 22, 2015
    • "2013). Moreover, the overexpression of LAMP-2A has been shown to restore CMA activity and reduce the levels of α-synuclein expression, thereby attenuating dopaminergic neurodegeneration with age (Xilouri et al., 2013). Therefore, interventions aimed at preventing the blockage of CMA through either increasing LAMP-2A expression, or decreasing the high binding affinity of mutant α-synuclein for LAMP-2A, may be a promising therapeutic strategy in PD. "
    [Show abstract] [Hide abstract] ABSTRACT: Caloric restriction (CR) is known to extend lifespan in most organisms, indicating that nutrient and energy regulatory mechanisms impact aging. The greatest risk factor for neurodegeneration is age; thus, the antiaging effects of CR might attenuate progressive cell death and avert the aggregation of abnormal proteins associated with neurodegenerative diseases. CR is a potent inducer of autophagy, a tightly regulated intracellular process that facilitates recycling of abnormal protein aggregates and damaged organelles into bioenergetic and biosynthetic materials to maintain homeostasis. Thus, dysregulated autophagy can lead to cellular dysfunction, abnormal protein accumulation, proteotoxicity and subsequently the onset of several neurodegenerative diseases. Therefore, the targeted and precision-controlled activation of autophagy represents a promising therapeutic strategy. Non-pharmacological therapeutic interventions that delay aging by modulating specific stages of autophagy might be beneficial against premature aging, neurodegeneration and its associated ailments. However, the dynamic and often compensatory cross-talk that exists between the protein degradation pathways makes clinical translational approaches challenging. Here we review the primary autophagy pathways in the context of age-related neurodegenerative diseases, focusing on compensatory mechanisms and pathway failure. By critically assessing each underlying molecular machinery, we reveal their impact on aging and unmask the role of caloric restriction in changing cellular fate by delayed aging through stimulation of autophagy. This may point towards novel and better targeted interventions that exploit the autophagic machinery in the treatment of neurodegenerative diseases.
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    • "Regarding the CNS, and the dopaminergic system in particular , we have recently shown that boosting CMA function through LAMP2A overexpression, both in neuronal cell systems and in the rat substantia nigra, effectively counteracted alpha-synuclein related toxicity (Xilouri et al., 2013 ). Importantly, in a model of AAValpha-synuclein-mediated nigral degeneration, targeted LAMP2A overexpression via AAV both increased the survival of nigral neurons and mitigated striatal terminal degeneration, while at the same time it reduced total alpha-synuclein levels and related aberrant species (Xilouri et al., 2013). This study highlighted an important role of CMA in alpha-synuclein pathobiology both in vitro and in vivo and suggested that modulation of the CMA pathway might represent a valuable therapeutic approach for the treatment of other synucleinopathies too, such as Multiple System Atrophy or Dementia with Lewy Bodies. "
    [Show abstract] [Hide abstract] ABSTRACT: The major lysosomal proteolytic pathways essential for maintaining proper cellular homeostasis are macroautophagy, chaperone-mediated autophagy (CMA) and microautophagy. What differentiates CMA from the other types of autophagy is the fact that it does not involve vesicle formation; the unique feature of this pathway is the selective targeting of substrate proteins containing a CMA-targeting motif and the direct translocation into the lysosomal lumen, through the aid of chaperones/co-chaperones localized both at the cytosol and the lysosomes. CMA operates at basal conditions in most mammalian cell models analyzed so far, but it is mostly activated in response to stressors, such as trophic deprivation or oxidative stress. The activity of CMA has been shown to decline with age and such decline, correlating with accumulation of damaged/oxidized/aggregated proteins, may contribute to tissue dysfunction and, possibly, neurodegeneration. Herein, we review the recent knowledge regarding the molecular components, regulation and physiology of the CMA pathway, the contribution of impaired CMA activity to poor cellular homeostasis and inefficient response to stress during aging, and discuss the therapeutic opportunities offered by the restoration of CMA-dependent proteolysis in age-associated degenerative diseases.
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    • "For instance, rapamycin and trehalose have been shown beneficial effects in toxic and genetic rodent models of PD (Dehay et al., 2010; Rodriguez-Navarro et al., 2010). Viral-mediated overexpression of Beclin-1, LAMP2a or TFEB has also proved therapeutic interest in rodent models overexpressing human -syn (Decressac et al., 2013; Spencer et al., 2009; Xilouri et al., 2013). Further validation in NHP is needed to fully confirm the therapeutic interest of such strategies (Dehay et al., 2015). "
    [Show abstract] [Hide abstract] ABSTRACT: Parkinson's disease is a common neurodegenerative disorder of unknown origin mainly characterized by the loss of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta and the presence of intraneuronal proteinaceous inclusions called Lewy bodies. Lysosomes are dynamic organelles that degrade, in a controlled manner, cellular components delivered via the secretory, endocytic, autophagic and phagocytic membrane-trafficking pathways. Increasing amounts of evidence suggest a central role of lysosomal impairment in PD aetiology. This review provides an update on how genetic evidence support this connection and highlights how the neuropathologic and mechanistic evidence might relate to the disease process in sporadic forms of Parkinson's disease. Finally, we discuss the influence of ageing on lysosomal impairment and PD aetiology and therapeutic strategies targeting lysosomal function.
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