Pathogenic lysosomal depletion in Parkinson’s disease
Journal of Neuroscience. 2010-09-15; 30(37): 12535-12544
DOI: 10.1523/JNEUROSCI.1920-10.2010
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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.