Are we starting to get closer to the truth... autophagy and lysosomal dysfunction giving rise to a synuclein predominant form of PD and all that goes with that (heavy non-motor and cognitive burden)... and a form characterised by mainly mitochondrial dysfunction with motor features as the main manifestation... significant overlap still probable and prion-like mechanisms remain a real possibility... who has looked at mitochondrial versus lysosomal function in RBD???
Mov Disord. 2016 Jan 27. doi: 10.1002/mds.26477. [Epub ahead of print]
Xilouri M, Brekk OR, Stefanis L.
Evidence from human postmortem material, transgenic mice, and cellular/animal models of PD link alpha-synuclein accumulation to alterations in the autophagy lysosomal pathway. Conversely, alpha-synuclein mutations related to PD pathogenesis, as well as post-translational modifications of the wild-type protein, result in the generation of aberrant species that may impair further the function of the autophagy lysosomal pathway, thus generating a vicious cycle leading to neuronal death. Moreover, PD-linked mutations in lysosomal-related genes, such as glucocerebrosidase, have been also shown to contribute to alpha-synuclein accumulation and related toxicity, indicating that lysosomal dysfunction may, in part, account for the neurodegeneration observed in synucleinopathies. In the current review, we summarize findings related to the inter-relationship between alpha-synuclein and lysosomal proteolytic pathways, focusing especially on recent experimental strategies based on the manipulation of the autophagy lysosomal pathway to counteract alpha-synuclein-mediated neurotoxicity in vivo. Pinpointing the factors that regulate alpha-synuclein association to the lysosome may represent potential targets for therapeutic interventions in PD and related synucleinopathies. © 2016 International Parkinson and Movement Disorder Society.
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