Lysosomal exocytosis of metastable proteins to control synaptic function

Introduction

The extreme length and small caliber of neuronal processes entail complex local regulation of protein turnover. In light of the high metabolic demand and dynamic protein exchange imposed by synaptic neurotransmission, several surveillance mechanisms should be in place to sense protein damage that will otherwise cause synaptic dysfunction.

Research Gap

However, it is still essentially unclear how local control of the metastable proteome, whose proteins have a high copy number and are crucial for synaptic function, is accomplished in dendrites to prevent the formation of toxic aggregates.

Previous Findings

My previous work suggests that neuronal activity drives lysosomal fusion with the plasma membrane and exocytotic release of supersaturated, aggregation-prone proteins. The deposition of these proteins in the interstitial space likely feeds into the glymphatic system and cleaning routines associated with the enhanced circulation of cerebrospinal fluid during sleep.

Intriguing Observations

Intriguingly, I could show that the concomitant release of lysosomal proteases enables the growth of spine synapses, suggesting that lysosomal exocytosis might serve both protein removal and synaptic plasticity, whereas the latter might be an inevitable consequence of the necessity for local disposal of aggregation-prone proteins.

Project Goals

Building on my expertise in synapse biology and advanced imaging, the LEXSYN project aims to:

1. Characterize the secretome of exocytotic lysosomes.
2. Understand the consequences of dendritic lysosomal fusion for synaptic plasticity.
3. Decipher physiological signals regulating lysosomal exocytosis.
4. Investigate the pathological consequences of lysosomal fusion impairment, thereby assessing its relevance in neurodegenerative diseases.

Methodology

To achieve these ambitious goals, I will develop new tools for monitoring and manipulation of dendritic lysosomal exocytosis in vivo.

Expected Outcomes

I expect to reveal mechanisms of fundamental relevance for the control of the metastable proteome and its contribution to neurodegeneration.