Pathogenic Lysosomal Depletion in Parkinson's Disease

By B. Dehay, J. Bové, N. Rodriguez-Muela, C. Perier, A. Recasens, P. Boya, M. Vila. Journal of Neuroscience, 2010

756 citations recorded by the source corpus.

Mounting evidence suggests a role for autophagy dysregulation in Parkinson's disease (PD). The bulk degradation of cytoplasmic proteins (including α-synuclein) and organelles (such as mitochondria) is mediated by macroautophagy, which involves the sequestration of cytosolic components into autophagosomes (AP) and its delivery to lysosomes. Accumulation of AP occurs in postmortem brain samples from PD patients, which has been widely attributed to an induction of autophagy. However, the cause and pathogenic significance of these changes remain unknown. Here we found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD that AP accumulation and dopaminergic cell death are preceded by a marked decrease in the amount of lysosomes within dopaminergic neurons. Lysosomal depletion was secondary to the abnormal permeabilization of lysosomal membranes induced by increased mitochondrial-derived reactive oxygen species. Lysosomal permeabilization resulted in a defective clearance and subsequent accumulation of undegraded AP and contributed directly to neurodegeneration by the ectopic release of lysosomal proteases into the cytosol. Lysosomal breakdown and AP accumulation also occurred in PD brain samples, where Lewy bodies were strongly immunoreactive for AP markers. Induction of lysosomal biogenesis by genetic or pharmacological activation of lysosomal transcription factor EB restored lysosomal levels, increased AP clearance and attenuated 1-methyl-4-phenylpyridinium-induced cell death. Similarly, the autophagy-enhancer compound rapamycin attenuated PD-related dopaminergic neurodegeneration, both in vitro and in vivo, by restoring lysosomal levels. Our results indicate that AP accumulation in PD results from defective lysosomal-mediated AP clearance secondary to lysosomal depletion. Restoration of lysosomal levels and function may thus represent a novel neuroprotective strategy in PD.

Subfields: Epidemiology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/32cbf1684ae1e80453a31ece4554ea78a49b99b1

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Citations in the corpus

A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB (2012, background): “Similarly, lysosomal membrane permeabilization observed in certain LSDs and neurodegenerative diseases may result in nutrient leakage and suppression of mTORC1 (Dehay et al , 2010; Kirkegaard et al , 2010).”
Parkinson disease: from pathology to molecular disease mechanisms. (2013, neutral): “The potential involvement of altered lysosomal function in PD was supported by studies in MPTP-treated mice [18,19].”
TFEB at a glance (2016, background): “…or pharmacological activation of TFEB in cellular and mouse models of Parkinson’s disease has been found to improve lysosomal function and ameliorate α-synuclein aggregation (Decressac et al., 2013; Dehay et al., 2010; Kilpatrick et al., 2015), which is a major hallmark of Parkinson’s disease.”
Lysosomal membrane permeabilization and cell death (2018, background): “somal alterations lead to decreased levels of lysosomal proteins, LMP and cathepsin release into the cytoplasm.(100,101) In these conditions,”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, neutral): “, 2004) as important initiators of PD (Dehay et al., 2010).”
TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity (2013, background): “In vitro and in vivo data suggest that increased expression of this transcription factor can be protective in models of protein misfolding and oxidative stress (7, 35, 40).”
Neuronal Cell Death. (2018, neutral): “In this instance, LMP and loss of lysosomes caused a secondary block in autophagosome activity (157, 694), which was recovered by inducing lysosomes biogenesis and/or reactivation of autophagy, both of which regenerated the lysosomes and ameliorated the toxicity.”
Etiology and pathogenesis of Parkinson's disease (2011, background): “In the MPTP-treated mouse, autophagosome accumulation occurs that is preceded by a marked decrease in the number of lysosomes in dopaminergic neurons because of abnormal permeabilization of lysosomal membranes caused by increased formation of ROS in mitochondria.(85) The linkage between MPTP/MPPþ-in”
Transcriptional Activation of Lysosomal Exocytosis Promotes Cellular Clearance (2011, background): “, 2009) and ameliorated the phenotype of cells from a murine model of Parkinson disease (Dehay et al., 2010).”