Front. Cell Dev: Bidirectional cycling between lysosomes and α-syn (bottom)

Lysosomal dysfunction exists in the brains of patients with Parkinson's disease, while the accumulation and aggregation of α-syn is the main pathogenesis of PD

Last week, we made a detailed interpretation of the first half of the article, Front.

5.

Protein form describes all protein variants encoded by a single gene, including post-translational modifications and sequence variants

6.

α-syn can be degraded by ALP and proteasome pathways

(1) Phosphorylation

Phosphorylation, which can occur on serine, threonine, and tyrosine side chains, is seen as a molecular on/off switch, but may also have effects on protein-protein binding properties and subcellular localization

(2) Oxidation

Oxidation is a covalent modification that modifies proteins directly through reactive oxygen species or indirectly through oxidative stress

(3) Dopamine modification

The main pathological changes in PD are progressive loss of dopaminergic neurons in the substantia nigra pars compacta accompanied by a decrease in striatal dopamine levels

(4) Aggregation

Several studies have shown that α-syn aggregates are cleared when cells begin the early steps of autophagy

7.

There are currently six known missense mutations in SNCA that directly suggest that α-syn is a causative factor in PD

(1) A53T

Missense mutations in α-syn-A53T can cause the protein to prevent self-degradation by occupying lysosomal binding sites with high affinity

(2) E46K

(3) A30P

8.

Lysosomes have the role of removing α-syn from the cytoplasm to maintain its homeostasis, and the protein form of α-syn can modulate deleterious effects on the ALP system, exacerbating dysfunction and ultimately disease

Figure 1: Reciprocal feedback loop of GCase inhibition and α-syn accumulation

9.

Includes α-syn RNAi and lysosomal enhancement
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10.
Summary

In conclusion, existing reports show a significant bidirectional relationship between lysosomes and α-syn, a complex and unstable pathogenic cycle that drives the development of neurodegenerative diseases
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references:

WildburgerNC, Hartke AS, Schidlitzki A and Richter F (2020) Current Evidence for aBidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms.
Front.
Cell Dev.
Biol.
8:598446.

Compilation Author: Level 10 Fatty (Brainnews creative team) 

Reviewer: Simon (Brainnews Editorial Office)