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Dysregulation of PINK1 & Parkin links Parkinson’s disease to autoimmune disease


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PINK1 and Parkin are two proteins that are commonly mutated in familial forms of Parkinson’s disease (PD) known as autosomal-recessive juvenile Parkinsonism (AR-JP).


A recent study has discovered that these two genes function as regulators of adaptive immunity (Matheoud et al., Cell 2016).


Under cellular stress conditions such as inflammation, PINK1 and Parkin repress mitochondrial antigen presentation (MitAP) by mediating the proteasomal degradation of Sorting nexin 9 (Snx9). In cells that lack functional PINK1 or Parkin, inflammation induces the formation of mitochondria-derived vesicles (MDVs) containing mitochondrial antigens.


This process requires Snx9 and Rab9 for MVD formation and Rab7 for fusion with the endosomal/lysosomal compartments. Antigens are processed in the lysosome and presented on MHC class I molecules at the cell surface of antigen presenting cells (APCs). Mitochondrial antigen-specific T lymphocytes are then activated through binding of T cell receptors to MHC class I molecules. Interestingly, dopaminergic (DA) neurons were shown to express MHC class I molecules in response to stressors linked to inflammation.


Dysfunction of the blood-brain barrier (BBB) observed in PD patients, and upregulation of MitAP in DA neurons may serve as a pathway to allow infiltration of autoreactive T cells into the brain. These cells can then recognize mitochondrial antigens on DA neurons, trigger cytotoxic responses and cell death.


These findings point to novel role for PINK1 & Parkin in linking autoimmunity to neurodegeneration.


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