Studying the lysosomal and proteasomal systems and their role in neurodegeneration and muscle homeostasis
Catastrophic, genetic neurodegenerative diseases in children are complex. Given such complexity, understanding the origin of disease is vital but challenging. To uncover these origins, we study a key organelle that serves as the digestive system of a cell: the lysosome. When the lysosome is unable to properly digest targeted molecular materials, these materials accumulate within a cell. Such abnormal accumulation leads to cell death and neurodegeneration. Through our study of the cell’s lysosomal system, we can broaden our understanding of deficient lysosomal function and how it results in catastrophic neurodegenerative disease in children and in the aging populations.
The lysosome is the main compartment of a cell that ensures balance between synthetic and degradative pathways. In our lab, we strive to deepen our understanding of this organelle, how its dysfunction contributes to pathogenesis in children, and how we can effectively develop therapeutic agents.
Our work focuses on genetically inherited lysosomal storage diseases, which allows us to dissect the mechanisms and pathways that lead to defects in lysosome function. Through a compelling basic-science program, our study of lysosomal disease models broadens our understanding of lysosomal enzyme function that controls degradation in a cell and other biological processes. Because a deficiency in these enzymes invariably leads to neurodegeneration, our research helps us understand the roots of (neuro)pathogenesis.
We begin our work with simple questions: what do these enzymes do, what do they target, and what are the consequences of their impaired function? To find these answers, we study diseases related to deficiencies in three lysosomal enzymes.
A study of three lysosomal enzymes
Cathepsin A, neuraminidase 1 (NEU1), and b-galactosidase (b-GAL) are three lysosomal enzymes that assemble into a high-molecular weight lysosomal complex. In this configuration, the enzymes modulate each other’s activity to optimally tackle the substrates they need to process. Because of their dependency on one another, single or combined deficiency in any of these three enzymes results in disease. Our goal is to dissect the features these enzymes share and uncover the unique aspects of pathogenesis in the associated diseases.
The impact of neuraminidase 1 deficiency – a key enzyme in cell physiology
While studying the cause of pathogenesis in a sialidosis model, we identified a previously unknown function of NEU1 that controls a ubiquitous process called lysosomal exocytosis. This process is primarily used by cells to repair their plasma membrane (PM) when small tears occur. It entails the movement of lysosomes to the site of damage at the PM, where they dock and eventually fuse with the PM. The docking step of the pathway is controlled by the lysosome-associated membrane protein (LAMP1), which is a natural substrate of NEU1. The fusion event results in the redistribution of lysosomal membrane proteins at the PM and releases part of the lysosome contents extracellularly.
Impaired functionality of lysosomal exocytosis links to several diseases. In contrast, in sialidosis, NEU1 deficiency provokes lysosomal accumulation of LAMP1 in an unprocessed sialylated state, which eventually causes lysosomes to dock in exceeding number at the PM, ready to fuse with the PM and abnormally release their contents extracellularly. This exacerbated lysosomal exocytosis, which occurs in cells of virtually all organs of the body and the nervous system, initiates and perpetuates a pathogenic cascade that leads to organ dysfunction and neurodegeneration. In neurons, for instance, the abnormal extracellular deposition of amyloid occurs via excessive lysosomal exocytosis, which in turn elicits a massive neuroinflammatory response.
Most importantly, this dysregulated pathway downstream of NEU1 deficiency can explain aspects of disease pathogenesis not only in this pediatric lysosomal disease but also in more common adult conditions, like Alzheimer’s disease, idiopathic fibrosis, and cancer. These studies are the main research focus in the d’Azzo laboratory.
In all our work, we strive to identify the correct starting point of pathogenesis in these genetic neurodegenerative diseases that raise awareness to the lysosomal system’s role in both pediatric and adult diseases. We apply a variety of approaches—ex vivo gene therapy, AAV-mediated therapy, enzyme replacement, drug therapy—that strive to restore enzyme function and aid the development of effective therapies for pediatric and adult diseases affecting the lysosomal system. A consistent, relentlessly curious approach guides all the work our laboratory leads.