Systems biology of neurodegenerative diseases

Abstract

Neurodegenerative diseases (NDs) collectively afflict more than 40 million people worldwide. The majority of these diseases lack therapies to slow or stop progression due in large part to the challenge of disentangling the simultaneous presentation of broad, multifaceted pathophysiologic changes. Present technologies and computational capabilities suggest an optimistic future for deconvolving these changes to identify novel mechanisms driving ND onset and progression. In particular, integration of highly multi-dimensional omic analytical techniques (e.g., microarray, mass spectrometry) with computational systems biology approaches provides a systematic methodology to elucidate new mechanisms driving NDs. In this review, we begin by summarizing the complex pathophysiology of NDs associated with protein aggregation, emphasizing the shared complex dysregulation found in all of these diseases, and discuss available experimental ND models. Next, we provide an overview of technological and computational techniques used in systems biology that are applicable to studying NDs. We conclude by reviewing prior studies that have applied these approaches to NDs and comment on the necessity of combining analysis from both human tissues and model systems to identify driving mechanisms. We envision that the integration of computational approaches with multiple omic analyses of human tissues, and mouse and in vitro models, will enable the discovery of new therapeutic strategies for these devastating diseases.

Figure 1

NDs are associated with broad physiologic responses in the CNS. A primary feature common to many NDs is the neuronal expression of intra- and/or extra-cellular aggregating protein (AP). Intra-neuronal APs, including α-synuclein, tau, the huntingtin protein, and superoxide dismutates-1 (SOD1), harm neurons directly by interfering with cellular processes, including microtubule and synaptic function.^– Extracellular APs, including amyloid-β, α-synuclein, and tau not only affect neurons, but stimulate responses from supporting cells (e.g., astrocytes and oligodendrocytes), and immune cells (e.g., astrocytes, and microglia). The supportive and immune cell response leads to production of reactive oxygen species (ROS) that are directly deleterious to neuron survival. Cytokines and other factors may also be directly harmful to neurons and promote BBB/BSCB leakiness.^,, Combined with enhanced cytokine production, the leaky BBB/BSCB enhances peripheral monocyte and leukocyte infiltration, contributing to homeostatic dysregulation.^, This figure was created using cell art adapted from Servier Medical Art (http://www.servier.com/Powerpoint-image-bank).