PINK1, A MITOCHONDRIAL KINASE, INTERACTS WITH A KEY AUTOPHAGIC PROTEIN: EXPLORING THE FIRST DIRECT CONNECTION BETWEEN MITOCHONDRIA AND AUTOPHAGY IN RECESSIVE PARKINSON’S DISEASE

This project represents the continuation of a Telethon-funded project focused on the characterisation of PINK1, a mitochondrial protein that when mutated cause autosomal recessive Parkinson’s disease (PD). The previous project produced important advances in the knowledge of PINK1 localization and function. Functional studies showed that PINK1 is a mitochondrial kinase, which resides in the inner mitochondrial membrane, and that its C-terminus region negatively controls autophosphorylation. We showed that PINK1 mutations can also cause late onset sporadic PD and that single heterozygous mutations are capable of inducing subclinical alterations also in healthy carriers. The yeast-two-hybrid experiments gave the most promising results, identifying Beclin1 as the first known PINK1 interactor. Intriguingly, Beclin1 is a key regulator of the autophagy machinery, a mechanism that has recently been indicated as a crucial protective strategy against neurodegeneration. Recent evidence indicates that down-regulation of autophagy results in a massive increase of neuronal cell loss both using in vivo and in vitro models, and that autophagy inductors are able to reduce proteic aggregates and toxicity in models of proteinopathies. The interaction between PINK1 and Beclin1 represents a direct link between a PD-related protein known to play a protective role against mitochondrial dysfunction and apoptosis, and a protein necessary to form autophagic vesicles. This novel project aims at fully characterising the physiological role of this interaction and the effects of PINK1 mutations in shifting the balance between apoptosis and autophagy towards apoptotic activation and cell death. These aims will be pursued using complementary approaches and distinct cellular models. This project holds the great potential to unravel a major protective mechanism against neurodegeneration, supporting current research for innovative therapeutic strategies in PD and other neurodegenerative conditions.