This is important stuff... evidence that alpha-syn accumulation affecting lysosomal degradation... lysosomes are responsible for much of the clearance of abnormal proteins from cells... so impairing lysosomal function could start a cycle of events leading to further accumulation and dysfunction... what's particularly exciting here is that the investigators show it is modifiable. Human midbrain models sound like a good idea too... this is the most affected part of the brain in PD!!
Proc Natl Acad Sci U S A. 2016 Feb 2. pii: 201520335. [Epub ahead of print]
Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D.
Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.
It is known that Parkinson's symptoms can be regressed and functions regained by taking oral palmitoyl ascorbate. It is possible that this mechanism is involved and testing it in vitro or in vivo would be useful.
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