Lysosomes and α-synuclein form a dangerous duet leading to neuronal cell death.
Front. Neuroanat.. 2014-08-14; 8:
DOI: 10.3389/fnana.2014.00083
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1. Front Neuroanat. 2014 Aug 14;8:83. doi: 10.3389/fnana.2014.00083. eCollection
2014.
Lysosomes and α-synuclein form a dangerous duet leading to neuronal cell death.
Bourdenx M(1), Bezard E(1), Dehay B(1).
Author information:
(1)Institut des Maladies Neurodégénératives, Université de Bordeaux, UMR 5293
Bordeaux, France ; CNRS, Institut des Maladies Neurodégénératives, UMR 5293
Bordeaux, France.
Neurodegenerative diseases are (i) characterized by a selective neuronal
vulnerability to degeneration in specific brain regions; and (ii) likely to be
caused by disease-specific protein misfolding. Parkinson’s disease (PD) is
characterized by the presence of intraneuronal proteinacious cytoplasmic
inclusions, called Lewy Bodies (LB). α-Synuclein, an aggregation prone protein,
has been identified as a major protein component of LB and the causative for
autosomal dominant PD. Lysosomes are responsible for the clearance of long-lived
proteins, such as α-synuclein, and for the removal of old or damaged organelles,
such as mitochondria. Interestingly, PD-linked α-synuclein mutants and
dopamine-modified wild-type α-synuclein block its own degradation, which result
in insufficient clearance, leading to its aggregation and cell toxicity.
Moreover, both lysosomes and lysosomal proteases have been found to be involved
in the activation of certain cell death pathways. Interestingly, lysosomal
alterations are observed in the brains of patients suffering from sporadic PD and
also in toxic and genetic rodent models of PD-related neurodegeneration. All
these events have unraveled a causal link between lysosomal impairment,
α-synuclein accumulation, and neurotoxicity. In this review, we emphasize the
pathophysiological mechanisms connecting α-synuclein and lysosomal dysfunction in
neuronal cell death.
DOI: 10.3389/fnana.2014.00083
PMCID: PMC4132369
PMID: 25177278