Plk2 promotes synaptic destabilization through disruption of N-cadherin adhesion complexes during homeostatic adaptation to hyperexcitation.

Synaptogenesis in the brain is highly organized and orchestrated by synaptic cellular adhesion molecules (CAMs) such as N-cadherin and amyloid precursor protein (APP) that contribute to the stabilization and structure of synapses. Although N-cadherin plays an integral role in synapse formation and synaptic plasticity, its function in synapse dismantling is not as well understood. Synapse weakening and loss are prominent features of neurodegenerative diseases, and can also be observed during homeostatic compensation to neuronal hyperexcitation. Previously, we have shown that during homeostatic synaptic plasticity, APP is a target for cleavage triggered by phosphorylation by Polo-like kinase 2 (Plk2). Here, we found that Plk2 directly phosphorylates N-cadherin, and during neuronal hyperexcitation Plk2 promotes N-cadherin proteolytic processing, degradation, and disruption of complexes with APP. We further examined the molecular mechanisms underlying N-cadherin degradation. Loss of N-cadherin adhesive function destabilizes excitatory synapses and promotes their structural dismantling as a prerequisite to eventual synapse elimination. This pathway, which may normally help to homeostatically restrain excitability, could also shed light on the dysregulated synapse loss that occurs in cognitive disorders.

The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson's disease data.

Open science and collaboration are necessary to facilitate the advancement of Parkinson's disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD.